With an incidence of 3-4.5 cases per million, adenoid cystic carcinoma (ACC) of the head and neck is one of the most common tumors of the parotid and sublingual salivary glands. In the clinical course, ACC is shown to have an aggressive long-term behavior, which leads to the fact that radical surgical resection of the tumor with tumor-free margins remains the "gold standard" in treating ACC. Particle radiation therapy and systemic molecular biological approaches offer new treatment options. However, risk factors for the formation and prognosis of ACC have not yet been clearly identified. The aim of the present review was to investigate long-term experience of diagnosis and treatment as well as risk and prognostic factors for occurrence and outcome of ACC.

Salivary gland cancers (SGCs) are relatively rare but comprise various histologic subtypes, which complicates design of prospective trials. Systemic chemotherapy plays a limited role in treatment of SGCs, but cisplatin and docetaxel showed efficacy in a previous preclinical study. Here, we conduct a prospective, phase II study to evaluate the efficacy and toxicities of cisplatin plus weekly docetaxel in patients with metastatic or recurrent SGC.

We included patients with histologically confirmed SGCs of the following subtypes: mucoepidermoid carcinoma, adenocarcinoma, ductal carcinoma, or adenoid cystic carcinoma. Patients had no prior systemic chemotherapy for metastatic or recurrent tumors and at least one measurable lesion. Patients were treated with docetaxel 35 mg/m2 (D1, 8) and cisplatin 70 mg/m2 (D1) every 21 days.

Forty-one patients were enrolled between April 2014 and October 2020. The median age was 58 years (range, 32 to 73 years). The most common histologic subtype was adenoid cystic carcinoma (63.4%), followed by ductal carcinoma (24.4%). The most common metastatic site was the lung (75.6%). The median treatment cycle was 5.5 (range, 3 to 8), and the objective response rate was 46.3%, with three complete responses. The median duration of response was 6.8 months (interquartile range, 4.0 to 10.2). The progression-free survival and overall survival were 9.4 months (95% confidence interval [CI], 8.4 to 10.5) and 28.2 months (95% CI, 22.7 to 33.6), respectively. There were no treatment-related deaths. The most common grade 3/4 adverse events were neutropenia (4.9%) and fatigue (4.9%).

Cisplatin plus weekly docetaxel is effective and tolerable with manageable toxicity as first-line therapy in patients with metastatic or recurrent SGC.

VEGF and HIF-1α are important regulators of angiogenesis, overexpressed in various tumors. Lacrimal gland Adenoid cystic carcinoma (ACC) is a malignant tumor whose angiogenic properties remain unexplored. This study was designed to evaluate the expression of HIF-1α and VEGF in lacrimal gland ACC.

VEGF and HIF-1α immunoexpression was undertaken in 30 lacrimal gland ACC cases. mRNA expression of VEGF and HIF-1α was analysed in 17 cases by quantitative real time PCR. The results obtained were correlated with clinicopathological features and survival of the patients to determine the prognostic significance.

Immunoexpression of HIF-1α and VEGF was seen in 36.6% and 46.6% ACC cases. HIF-1α expression showed significant association with advanced T-stage (P = 0.001) and VEGF with intracranial extension (P = 0.014) and solid histological pattern (P = 0.045). HIF-1α mRNA expression was seen in 29.4% cases and showed significant association with perineural invasion (P = 0.027). Recurrence occurred in 60%, distant metastasis in 20% and death in 20% cases. Survival analysis revealed that patients with HIF-1α, VEGF immunoexpression, solid histological pattern, perineural invasion, bone erosion, intracranial extension, metastasis, advanced T-stage, and exenteration had poor survival. On multivariate analysis VEGF immunoexpression (hazard ratio, 16.785; 95% confidence interval, 1.872-150.495; P = 0.012) was the most significant poor prognostic factor.

This study demonstrates that VEGF is a potential predictor for poor clinical outcome in lacrimal gland Adenoid cystic carcinoma.

Adenoid cystic carcinoma (ACC) is a rare tumor, usually arising in the salivary gland, accounting for 1% of all head and neck cancers. ACC may have a long-term poor prognosis, as about 40% of radically treated patients will recur locoregionally and up to 60% will develop distant metastasis. Factors influencing risk of recurrence have been well studied, but few data exist about prognostic factors in Recurrent/Metastatic (RM) setting. Moreover, treatment of RM ACC is often a challenge for clinicians, in the context of a rare disease, which may have an indolent clinical behavior or less frequently a quicker growth and with a paucity of available clinical trials. This review critically analyzes pathological and molecular prognostic factors in RM ACC and make an overview on actual therapeutic choices and future direction of therapy. Recognized prognostic factors in RM ACC are the presence and site of distant metastasis (lung vs other), the presence of nodal metastasis and of extranodal extension, skull base recurrence, disease free interval, lymphovascular invasion, solid histotypes and grading of disease, and the presence of mutation of NOTCH1 family, PI3K, and TP53. Due to disappointing results with chemotherapy, new approaches are under study, also on the basis of biomolecular research. Ongoing clinical trials are evaluating treatment targeting MYB and NOTCH1 alterations, immunotherapy or combination of targeted treatments and immune checkpoint inhibitors.

Salivary gland carcinomas (SGCs) account for <5% of head and neck malignant neoplasms, further subcategorized in over 20 histological subtypes. For the most part, treatment for advanced disease is guided by morphology. SGCs in general respond poorly to a wide array of standard chemotherapy, with short durability, and significant toxicity. More recently, next-generation sequencing provided significant input on the molecular characterization of each SGC subtype, not only improving diagnostic differentiation between morphologically similar tumor types but also identifying novel driver pathways that determine tumor biology and may be amenable to targeted therapy. Among the most common histological subtype is adenoid cystic carcinoma, which often harbors a chromosome translocation resulting in an MYB-NFIB oncogene, with various degrees of Myb surface expression. In a smaller subset, NOTCH1 mutations occur, conferring a more aggressive pattern and potential sensitivity to Notch inhibitors. Salivary duct carcinomas may overexpress Her-2 and androgen receptors, with promising clinical outcomes after exposure to targeted therapies approved for other indications. Secretory carcinoma, previously known as mammary analog secretory carcinoma, is distinguished by an ETV6-NTRK3 fusion that can both help differentiate it from its morphologically similar acinar cell carcinoma and make it susceptible to Trk inhibitors. In the present article, we discuss the molecular abnormalities, their impact on tumor biology, and therapeutic opportunities for the most common SGC subtypes and review published and ongoing clinical trials and future perspectives for this rare disease.

Salivary gland cancers represent a rare group of tumors composed by over 20 histological subtypes. Initially treated as one single disease, its diagnosis, prognosis, and treatment are currently being stratified based on morphology. More recently, insight has been provided on the molecular characterization of each subtype, further improving diagnostic accuracy and paving the way for personalized therapy. In this article, we provide a comprehensive review of recent breakthroughs, preliminary results of novel therapy, and future directions on the treatment of these complex malignancies.

We investigated the expression of neuropilin-1 (NRP1), neuropilin-2 (NRP2), vascular endothelial growth factor-A (VEGF-A), semaphorin-3A (Sema-3A), and semaphorin-3F (Sema-3F) in normal salivary gland (NSG) tissue, nonmetastatic salivary adenoid cystic carcinoma (SACC), and metastatic SACC to better understand their role in intratumoral angiogenesis and hematogenous metastasis of SACC.

The study included 60 SACC patients, equally divided between nonmetastatic SACC and metastatic SACC. We used 30 NSG samples as the control. The expression of cytokines was studied by immunohistochemistry and compared using the integrated optical density. The relationship between NRP1, NRP2, VEGF-A, and Sema-3A expression and microvessel density (MVD) was analyzed in the 3 groups.

In metastatic SACC, the expression levels of NRP1 and VEGF-A were significantly greater than those in nonmetastatic SACC and NSG. The expression of Sema-3A and Sema-3F was significantly lower in metastatic SACC than that in nonmetastatic SACC and NSG (P < .0001). No significant differences were found in NRP2 expression among the 3 groups (P = .43). The MVD of metastatic SACC was significantly greater than that of nonmetastatic SACC and NSG (P < .0001). However, the lymphatic vessel density of the 3 groups was not significantly different statistically. The relationship between MVD and NRP1 or VEGF-A showed a significant positive correlation (P < .0001, for both). However, a significant negative correlation was found between the MVD and Sema-3A or Sema-3F expression (P < .0001, for both).

Hematogenous metastasis of SACC is correlated with high expression of NRP1 and VEGF-A and low expression of Sema-3A and Sema-3F. The increased numbers of microvessels induced by VEGF-A signaling, combined with NRP1, could be one of the key reasons leading to the enhanced hematogenous metastasis in SACC.

Salivary gland carcinomas (SGCs) represent one of the most complex tumors from a pathological point of view. According to the World Health Organization (WHO) classification (2005), twenty-four malignant histotypes are recognized, almost all characterized by specific morphological and genetic features as well as by particular clinical behavior. Loco-regional relapse and distant metastases are quite common. Distant metastases are diagnosed in 25-55% of the patients and only 20% of them are alive after 5years. Adenoid cystic carcinoma (ACC) is the most common (60%) malignant histotype observed in patients with metastatic disease, whilst the other histotypes such as mucoepidermoid carcinoma, salivary duct carcinoma, adenocarcinoma, not otherwise specified (NOS), and myoepithelial carcinoma are rarer. The most common therapeutic approach in cases of metastatic disease is systemic chemotherapy, although the results with this type of approach are poor both in terms of response rate and overall outcome. No consensus has yet been reached on what the standard regimen of chemotherapy should be in this setting. New therapies are under investigation e.g. antiangiogenic agents, histone deacetylase inhibitors, and hormonal deprivation treatment. We have focused our review on systemic treatments in ACC and in non-ACC tumors, including in this latter group all SGC histotypes other than ACC.

This article provides an update on the current understanding of adenoid cystic carcinoma of the head and neck, including a review of its epidemiology, clinical behavior, pathology, molecular biology, diagnostic workup, treatment and prognosis. Adenoid cystic carcinoma is an uncommon salivary gland tumor that may arise in a wide variety of anatomical sites in the head and neck, often with an advanced stage at diagnosis. The clinical course is characterized by very late recurrences; consequently, clinical follow-up should extend at least >15 years. The optimal treatment is generally considered to be surgery with postoperative radiotherapy to optimize local disease control. Much effort has been invested into understanding the tumor's molecular biological processes, aiming to identify patients at high risk of recurrence, in hopes that they could benefit from other, still unproven treatment modalities such as chemotherapy or biological therapy.

Salivary gland tumors (SGTs) consist of a heterogeneous group of lesions accounting for 3% to 10% of all head and neck neoplasms. Little is known about their angiogenic properties, and despite vascular endothelial growth factor (VEGF) has been previously studied in these lesions, further investigations are warranted to better determine its clinical and prognostic significance. In the current study, a total of 132 formalin-fixed, paraffin-embedded SGTs were organized in tissue microarray blocks and submitted to immunohistochemistry against VEGF protein. Slides were scanned and immunoreactions analyzed using Pixelcount V9 algorithm (Aperio Technologies Inc, Vista, CA, USA). Clinical and follow-up data were retrieved from patients' medical charts. Tumors included 50 cases of pleomorphic adenoma, 32 mucoepidermoid carcinomas, 30 adenocarcinomas not otherwise specified, and 20 adenoid cystic carcinomas. A slight male preponderance was found (1.1:1.0), with a mean age of 47.5 years. Parotid gland was the most affected location. Vascular endothelial growth factor expression was found in the cytoplasm of all cases analyzed with variable intensity, proving to be overexpressed in malignant tumors if compared with pleomorphic adenoma. A significant correlation of VEGF reactivity was found only with age, showing no further significant associations. Age and presence of paresthesia were the only features that predicted a lower specific survival rate under univariate and multivariate analyses. Log-rank test evidenced VEGF high expression as a potential determinant of reduced survival, although a statistical significance could not be reached. Hence, considering VEGF overexpression in malignant tumors and its potential association with a lower survival rate, this protein might be associated with SGTs pathogenesis and aggressiveness.

Recent research suggests that multinodular recurrent pleomorphic adenoma (PA) might result from cell migration through lymphatics. Lymphangiogenesis in malignancies is mediated by vascular endothelial growth factors C and D (VEGF-C/D). We studied the expression of VEGF-C/D in PA by immunohistochemistry as well as lymphatic vessel density (LVD). In 6 non-recurrent, 4 primary-to-recur, and 10 recurrent PAs, VEGF-C/D expression was assessed by immunohistochemistry. Staining was scored in terms of staining intensity (0 = absent to 3 = strong), and the percentage of positive tumor cells (scored as 0 (0-19 %), 1 (20-39 %), 2 (40-50 %), and 3 (60-100 %)) and a sum score were calculated. Intra- and peritumoral LVD was assessed by counting of LV after immunostaining, using the D2-40 antibody. All but one sample were VEGF-C negative. The differences in VEGF-D expression between non-recurrent, primary-to-recur, and recurrent PAs were not significant (p>0.05). VEGF-D expression did not correlate with peritumoral LVD (p>0.05). Our study revealed a significant difference between intra- and peritumoral LVD values when comparing individual and all sample groups (p=0.01). The lack of VEGF-C expression and of significant differences in VEGF-D expression and peritumoral LVD between patients with non-recurrent, primary-to-recur, and recurrent PAs does not support the lymphangiogenic local spread hypothesis

This study investigates whether salivary tumours with different morphology and evolution also differ in terms of neovascularization and VEGF expression and the prognostic value of the results. Surgical specimens from 45 patients - 8 pleomorphic adenomas (PA), 7 Warthin tumours (WT), 5 basal cell adenomas (BA), 6 carcinomas ex-pleomorphic adenoma (CEPA), 6 mucoepidermoid carcinomas (MEC), 5 acinic cell carcinomas (AC), 4 adenoid cystic carcinomas (ACC) and 4 adenocarcinomas not otherwise specified (ADK NOS) - were immunostained. In malignant salivary tumours, the following mean microvascular density (MVD) values were recorded (± SD = Standard Deviation): 27.61 (SD ± 2.27) in cases with CEPA, 27.08 (DS ± 7.81) in AC and 32.93 (SD ± 7.76) in ADK NOS, with lower values for MEC 24.31(SD ± 2.88) and for ACC 22.13 (SD ± 5.44). For benign tumours, an MVD of 35.71 (SD ± 2.09) was recorded in WT and lower average values in PA (MVD = 14.84; SD ± 4.86) and in BA (MVD = 23.96; SD ± 9.13). MVD did not correlate with the investigated clinicopathological parameters. The VEGF expression is significantly more important (p = 0.001) in malignant salivary tumours as compared with benign ones. The VEGF expression and the microvascularization in salivary gland tumours are important elements to be considered when formulating a diagnosis and assessing case evolutions in patients with such tumours.

Claudins are transmembrane proteins of tight junctions emerging as targets for diagnosis, prediction of prognosis, disease recurrence, and metastasis. Our goal was to evaluate expression of claudin-4 in the most common benign and malignant salivary gland neoplasms.

Claudin-4 gene levels and protein expression were determined by real-time polymerase chain reaction (PCR), and immunohistochemistry in a total of 30 specimens containing normal salivary tissue, pleomorphic adenoma, Warthin's tumor, mucoepidermoid carcinoma, and adenoid cystic carcinoma.

We identified down-regulation of claudin-4 gene levels and protein expression from normal control to benign salivary gland neoplasms and reached their lowest values in the malignant salivary gland neoplasms.

Low claudin-4 expression could be considered as a sign of increasing cellular disorientation and invasion of salivary gland tumors.

Adenoid cystic cancer arising in the salivary glands has distinctive features such as perineural invasion, distant metastasis, and a variable prognosis. In salivary gland cancer, c-kit, EGFR, and VEGF are representative molecular markers that may predict remnant and recurrent tumors. In this study, the expression of c-kit, EGFR, and VEGF in adenoid cystic cancer was evaluated, and the relationships between the expression of these markers and the clinical findings were investigated.

The medical records of 48 patients who were treated for parotid adenoid cystic cancer from January 1990 to January 2006 were reviewed. The tumor location, size, histological subtypes, perineural invasion, the resected margin status, and lymph node metastasis were assessed. Immunohistochemical staining and semiquantitative analysis of c-kit, EGFR and VEGF were performed. The relationship between the expression of each marker and the clinicopathological factors were analyzed.

Positive c-kit immunostaining was present in 45 patients (94%), with weak positivity (+1) in 23, moderate positivity (+2) in 19 and strong positivity (+3) in three. Positive EGFR immunostaining was observed in 27 (56%), with weak positivity (+1) in 19 and moderate positivity (+2) in eight with no strong positive staining. Positive VEGF immunostaining was present in 42 patients (88%) with weak positivity (+1) in 12, moderate positivity (+2) in 17, and strong positivity (+3) in 13. Only the expression of VEGF was significantly higher in parotid gland tumors than in any other gland (P = 0.032). Marginal involvement was associated with strong VEGF expression (P = 0.02). No marker was significantly correlated with recurrence or the survival rate. Lymph node status was related to the survival rate.

The expression of c-kit, EGRF, and VEGF had no predictive value for recurrence or the prognosis of adenoid cystic cancer. Only the lymph node status was related to the prognosis.

The correlation between vascular endothelial growth factor (VEGF) overexpression and the clinical outcome of head and neck cancer remains inconclusive. This meta-analysis aimed to evaluate the prognostic value of VEGF in patients with head and neck cancer.

We searched Ovid MEDLINE, EMBASE and 2 Chinese science databases in order to enroll all eligible articles. Forty-seven studies were included in this meta-analysis. All results were evaluated by the random-effects model.

VEGF overexpression is significantly associated with worse overall survival (OS; hazard ratio [HR], 1.89; 95% confidence interval [CI], 1.61-2.22) and progression-free survival (PFS; HR, 1.68; 95% CI, 1.33-2.12). Subgroup analysis reveals that VEGF overexpression is a significant poor predictor for nasopharyngeal cancer (HR, 1.66; 95% CI, 1.30-2.12) and salivary gland cancer (HR, 3.32; 95% CI, 1.61-6.84).

Our meta-analysis supports that VEGF overexpression is an available poor predictor for patients with head and neck cancer.

Cysteine-rich protein 61 (Cyr61) selectively binds heparin and insulin-like growth factors and mediates a variety of biological actions, including cell adhesion, differentiation, proliferation, migration, angiogenesis, and tumorigenesis. Cyr61 is also a prognostic factor for tumor progression and survival of individuals with various types of tumors. This study investigated the relationship between the expression level of Cyr61 and clinicopathological features, as well as the prognostic significance of Cyr61 expression in human salivary adenoid cystic carcinoma (SACC). The expression of Cyr61 and Ki-67, a cell-proliferation marker, was examined immunohistochemically in paraffin embedded tissue specimens from 60 SACC patients who underwent radical surgery between 1995 and 2004. A chi-square test was used to investigate the relationship between Cyr61 and Ki-67 expression and clinicopathological features. Survival analysis was performed to determine the prognostic significance of Cyr61 expression. Cyr61 expression was observed in 39 cases (39/60, 65%) of SACC, and Cyr61 expression was positively correlated with Ki-67 expression (P=0.002). A high expression of Cyr61 was significantly associated with solid subtype, perineural invasion, vascular invasion or cancer embolus, advanced stage, recurrence, and metastasis (P<0.05). The survival rate of patients with high expression of Cyr61 or Ki67 was significantly lower than that of patients with low expression. Multivariate Cox's proportional hazards analysis showed that vascular invasion, TNM stage, recurrence, distant metastasis, Ki-67 expression, and Cyr61 expression were independent prognostic factors of overall survival (P<0.05). Cyr61 expression is significantly correlated with Ki-67 expression and may have potential value in screening high-risk cases for recurrence and metastasis, as well as identifying poor prognosis in SACC patients.

Metastasis of salivary gland tumors has a negative impact on survival. Angiogenesis and its factors are potential markers for predicting metastasis in different malignant tumors, but this is not the case for salivary gland tumors.

Salivary gland tumors of distinct biologic behavior were analyzed according to the semiquantitative immunoexpression of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP).

Vascular endothelial growth factor expression was predominantly weak in benign tumors. Weak TP expression was observed in 100% cases of benign tumors and in 74.3% of primary malignant tumors. High VEGF and TP expression levels were significantly associated with primary malignant tumors but not with primary non-metastasizing and primary metastasizing malignant tumors or with subtypes of malignant tumors.

Vascular endothelial growth factor and TP expression levels discriminate benign and malignant tumors but cannot predict metastasis from non-metastasizing tumors.

In this review we present recent progress in diagnostic workup, prognostic evaluation, treatment options and resulting outcomes. Whenever possible, complete resection remains the mainstay of treatment. Sacrifice of facial nerve branches is reserved for the clinically or electromyographically dysfunctioning facial nerve. Clinical or radiological neck disease demands combined surgery and radiotherapy. Treatment of the N0 neck is indicated for advanced stage-high grade tumors but the question remains unanswered whether this should be surgical or radiotherapeutic elective treatment. Surgery alone will cure low stage, low grade tumors, that show no additional negative prognostic factors following adequate resection. In all other tumors postoperative radiotherapy will improve locoregional control. This approach results in good locoregional control, in a way that distant metastasis remains the typical presentation of treatment failure. In this setting, the results of systemic treatment today remain limited, but a huge effort in the molecular biology field has been done to introduce targeted therapy into this domain of head and neck cancer. Disease control remains variable within the patient population. This variation can increasingly be predicted by systems that incorporate the combined information of multivariately identified and quantified prognostic factors into an individualized prognosis for the parotid carcinoma patient.

Adenoid cystic carcinoma (ACC) of the salivary gland is characterized by a prolonged but inevitably unfavorable clinical course. Recent studies have suggested that the transmembrane tyrosine kinase receptor, c-kit proto-oncogene is involved in ACC pathogenesis. CD43 is a sialoglycoprotein that is typically expressed by hematopoietic cells and their derivative neoplasms, although positivity in epithelial tumors has only been recognized recently.

The aim of this study was to evaluate c-kit and CD43 immunoreactivity in ACCs and to compare the extent of their expression in various histologically defined subgroups of ACC, and their probable involvement in ACC pathogenesis.

Formalin-fixed paraffin-embedded sections from 35 ACCs were immunostained for c-kit and CD43 using monoclonal antibodies.

Cytoplasmic and membranous c-kit immunoreactivity was detected in 25/35 ACCs (71.4%) with strong immunostaining observed in solid pattern of ACC. Cytoplasmic and membranous CD43 immunoreactivity was detected in 18/35 (51.4%) of ACCs with strong immunostaining seen in the cribriform pattern.

These results suggested that c-kit could be used as a prognostic marker for ACC and specific c-kit tyrosine kinase inhibitors such as imatinib, might be used in future therapeutic approaches against subgroups of ACC. CD43 appears to be preferentially expressed in salivary gland ACCs. Its expression decreased with cellular dedifferentiation and there was an inverse relationship between immunoexpression of c-kit and CD43 among ACC of salivary gland.

Defects in the mitotic checkpoint lead to aneuploidy and might facilitate tumorigenesis. However, the ploidy status in salivary duct carcinoma (SDC) has been reported to play limited role in prediction of prognosis. Thus, we need more reliable markers to reflect the rapid tumor progression in SDCs. We aimed here to investigate the expression of mitotic checkpoint proteins benzimidazole 1 homolog beta (BUB1B) and mitosis arrest-deficient 2 like 1 (MAD2L1) in SDCs and to determine their possible role as surrogate prognostic markers.

We analyzed the clinical courses, pathologic findings and immunohistochemical profiles of mitotic checkpoint proteins (BUB1B and MAD2L1) in 27 pathologically confirmed SDCs. The expression status of BUB1B and MAD2L1 was compared with clinicopathologic factors and other molecular markers, such as TGF-beta, c-erb-B2, androgen receptor, vascular endothelial growth factor, and epidermal growth factor receptor, for prognostic significance.

High BUB1B expression was detected in 25.9% of subjects, and high MAD2L1 expression was in 55.6% of subjects. However, survival analysis revealed that mitotic checkpoint expression did not have prognostic significance in SDCs, nor did the other studied markers. Rather, the clinical variable of N classification at diagnosis (in N+ status, hazard ratio 5.19, 95% CI 1.26-21.32 for disease-free survival and hazard ratio 7.18, 95% CI 1.09-46.99 for overall survival) was strongly associated with survival and prognosis based on the Cox proportional hazard model.

Mitotic checkpoint proteins appeared to play a limited role in predicting prognosis in SDCs. Further study is required to elucidate the exact role of mitotic checkpoint proteins in SDCs.

The proliferative capacity of a tumor as measured by Ki-67 nuclear antigen is one of the most powerful indicators of tumor behavior. Ki-67 is considered a useful tool in determining the aggressiveness of malignant neoplasms. p53 tumor suppressor gene mutations have been linked with the development and progression of a number of various cancer types. p53 tumor suppressor protein and the volume corrected index of Ki-67 corresponding to Ki-67 /mm2 of tumor tissue (VCI Ki-67) in salivary gland tumors were evaluated by immunohistochemistry from paraffin embedded sections in a series of 212 patients. The follow-up time in this nationwide full population-based study was up to five years. The association of clinicopathological features and the results of present study with survival were examined. In multivariate analysis high VCI Ki-67 was associated with worse survival of SGC patients (p = 0.0114). Supplementary information was brought by age (p = 0.0002), lymph node status (p = 0.0014), gender (p = 0.0017) and stage (p = 0.0191). p53 expression did not have additional value in prediction of survival (p = 0.1433) compared to the commonly clinical used parameters. In this material consisting of various salivary gland carcinomas VCI Ki-67 was a good prognostic factor for survival.

The treatment of relatively rare malignancies, such as those of the salivary glands and iodine refractory thyroid cancer, has been invigorated by the development of novel molecular targeting agents. Accrual to clinical trials for these disease sites continues to be limited by their relatively low incidence. Nonetheless, multicenter collaborations have contributed greatly to the development of a number of emerging systemic therapies. This article briefly summarizes the epidemiology and pathogenesis of salivary gland and thyroid cancer, and then describes some of the new drugs under evaluation for these malignancies.

Salivary gland tumors are a rare and clinically diverse group of neoplasms that represent less than 1% of all malignancies. In locoregional recurrent or metastatic disease, systemic therapy is the standard approach. Numerous phase II studies with small sample sizes have assessed the activity of different cytotoxic agents, either alone or in combination. For these agents, the objective response rates are generally modest, ranging from 15% to 50%. Duration of response is typically cited in the range of 6 to 9 months. Further evaluation of novel therapies is mandated in this disease. With the emergence of molecular targeted therapy, these tumors become optimal candidates for trials of investigational drugs and established drugs for new indications. Often, salivary gland carcinomas are indolent. As such, one should wish only to treat patients with progressive disease. Study designs must incorporate stringent inclusion criteria to enable accurate reporting of disease response and stabilization, especially in the evaluation of new drugs and novel combinations. Salivary gland-focused cooperative groups are necessary in order to accrue patients to these clinical trials and establish new treatment guidelines for these patients.

Salivary gland neoplasms are composed of histopathologically and clinically diverse entities. The reported response rates of salivary gland tumors to chemotherapy are generally poor. Molecular studies have provided some information on their biology and have identified new targets with therapeutic potential.

Several agents are currently being tested that target molecular signaling and cancer cell biology. The pathways involved include but are not limited to vascular endothelial growth factor and epidermal growth factor receptors. Novel treatments under evaluation include tyrosine kinase inhibitors, antibodies, angiogenesis inhibitors, demethylating agents, and proteasome inhibitors.

Some of these new targeted approaches hold promise for our future ability to treat patients with salivary gland cancer unresponsive to traditional therapy, but others were disappointing. The presence of the molecular target alone is not sufficient to guarantee an antitumor effect with targeted therapy. The success of these molecular-targeted agents depends on the molecular abnormalities involved in carcinogenesis.

Salivary gland cancers are relatively rare and quite diverse. Current therapy relies on local ablation. There are few large clinical trials or randomized trials to guide treatment, especially for metastatic disease. This article reviews the epidemiology, staging, molecular characteristics, and treatment evidence for the most common types of salivary cancers and suggests potential future diagnostic and treatment directions. Progress in understanding the molecular and cell biology of salivary gland cancers may lead to the development of targeted therapies in these rare tumors. Multidisciplinary and multi-institutional collaborative studies are needed to help improve survival in salivary gland cancers.

This is a review about recent clinical developments in rare cancers of the head and neck.

Progress in molecular biology techniques has allowed the identification of new prognostic factors, and potential molecular-targeted therapies. This is of importance since chemotherapy continues to play a role but is still limited in this group of malignancies. New techniques of irradiation such as intensity-modulated radiotherapy and three-dimensional conformal radiotherapy appear to improve the locoregional control of these tumors. Surgery continues to be the cornerstone of treatment, with a growing interest in the technique of sentinel lymph node biopsy.

As salivary gland carcinomas, paranasal sinus cancers and melanoma of the head and neck are rare malignancies, these tumors must be treated in specialized anticancer centers with access to the latest surgical and irradiation techniques. Moreover, clinical studies with translational research are needed to identify strong prognostic and predictive factors, and effective molecular-targeted therapies.

The purpose of this study was to estimate the possibility of using thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and p53 as predictive values of clinical outcome in adenoid cystic carcinoma (ACC). The expressions of TS, DPD, and p53 were examined with immunohistochemistry in 27 ACC patients, and the association with clinicopathological factors was determined. Cases with high DPD expression had significantly higher distant metastasis rates compared to those with low DPD expression (p=0.001), whereas neither TS nor p53 expression showed any significant correlation to clinicopathological factors. Interestingly, six of 14 early-stage patients had distant metastases and all of their tumors showed high DPD expression. Kaplan-Meier analysis revealed that a solid histological pattern and distant metastasis correlated with a poor prognosis. In early-stage patients, whose tumor was completely resected, those with high TS or DPD expression had a worse prognosis compared to those with low expression, but the difference did not reach statistical significance (TS, p=0.178; DPD, p=0.251). Our results suggest that assessment of DPD expression in ACC may be a useful tool in determining the mode of treatment as well as evaluating clinical outcome.

The vascular endothelial growth factor (VEGF) and p53 play important roles in the growth of tumor. However, the relationship between the expression of VEGF and p53 and tumor cell proliferation in human gastrointestinal cancer remains unknown. In the present study, therefore, we have examined the relationship between VEGF and p53 expression and tumor cell proliferation in gastrointestinal carcinoma (GITC), as well as the association between these biomarkers and clinicopathological factors.

Surgical specimens from 30 patients with GITC were examined for VEGF, p53, and proliferating cell nuclear antigen (PCNA) expression by immunohistochemical staining.

We found a predominant VEGF expression of moderate intensity in 16(54.84%) of 30 GITC cases, while p53 expression was mainly high in 13(45.16%) of 30 GITC cases. PCNA expression was high in 20(64.52%) of 30 GITC cases. Tumor size, infiltration, vascular invasion, and gastritis were significantly correlated with VEGF, p53, and PCNA expression. There was a significant correlation between VEGF and p53 expression (P = 0.0001), VEGF and PCNA expression (P = 0.00004), and between p53 expression and PCNA expression (P = 0.0016). When the VEGF and p53 expression, and PCNA expression were considered together, both VEGF and p53 expression were not significantly associated with PCNA. A significant correlation between the PCNA expression and the mitotic index (P = 0.0016) was also found.

These results demonstrate that VEGF and p53 expression are significantly correlated as independent prognostic factors with tumor cell proliferation, and might be associated with relevant events involved in gastrointestinal tumor biology.

Although cancers arising in the head and neck region are a diverse group of malignancies, a unifying thread remains a poor overall survival for patients with advanced, recurrent or metastatic disease. Treatment strategies need to evolve and improve upon established therapeutic practices. As the process of cancer evolution is understood to be derived from aberrations in genetic and epigenetic processes, molecularly targeted agents offer attractive therapeutic options by restoring normal control of oncogenic processes. The direct role for the treatment of squamous cell carcinoma of the head and neck, nasopharynx and salivary gland carcinomas with these novel, molecularly targeted agents are reviewed and their potential to improve on the existing standard of care is further explored.

Salivary gland cancers include tumors of different histologic characteristics and biological behavior. Radical surgery, followed or not by radiation therapy, represents the main treatment approach for this disease. The role of systemic chemotherapy is less clearly defined since trials of single-agent chemotherapy have consistently shown low response rates. Polychemotherapy is likely to induce a higher response rate, but does not improve survival. The determination of the molecular abnormalities underlying the different subtypes of salivary gland cancers might lead to more active targeted therapies. C-kit is overexpressed in a wide percentage of salivary gland carcinomas, but clinical trials with single-agent imatinib have been negative. ErbB1 and ErbB2 are also frequently overexpressed in salivary gland cancers and this has provided the rationale for clinical trials with trastuzumab, cetuximab, gefitinib, lapatinib. Finally, new pathways, such as vascular endothelial growth factor, might be worth targeting and clinical trials with anti-angiogenic agents are ongoing.