Salivary gland tumor

Epidemiological and statistical data concerning such a disease as salivary gland tumor have not been registered until recently. The main reasons for this fact were: lack of separate statistical records; association with other malignant neoplasms of the upper digestive tract, as well as statistical errors, demographic differences and other local factors.

Thus, according to the consolidated data of Oxford University, in 1963-1980, salivary gland tumors occurred with a frequency of 0.4 to 13.5 per 100,000 population in Uganda, Malaya, Malawi, Scotland and Greenland. Malignant salivary gland tumors vary from 0.4 to 2.6 per 100,000 population. In the USA, malignant salivary gland tumors account for up to 6% of all head and neck cancer cases and up to 0.3% of all malignant neoplasms.

The main morphological form among benign neoplasms is a benign tumor of the salivary gland - pleomorphic adenoma (85.3%), with 86% of pleomorphic adenomas localized in the parotid, 6% - in the submandibular, 0.1% - in the sublingual, 7.8% - in the minor glands. The second place in frequency is occupied by adenolymphoma (9.2%), the share of other morphological types of adenomas accounts for 5.5%. Among carcinomas, the predominant role belongs to adenoid cystic (33.3%), with 59.4% developing in the minor, 29% - in the parotid, 10% - in the submandibular, and 1.6% - in the sublingual gland.

According to the US National Cancer Registry, malignant tumors of the salivary gland account for 6 cases per 1,000,000 population.

What causes salivary gland tumors?

The causes of salivary gland tumors are unknown, however, as with other neoplasms, the role of harmful environmental factors and genetic abnormalities is considered. Salivary gland tumors are currently associated with inflammatory diseases, alimentary factors, hormonal and genetic disorders. There is data on the role of epidemic parotitis, factors confirming the transmission of inherited changes in the parenchyma of the salivary gland, as well as changes in the process of embryogenesis, have been identified.

Among the harmful environmental factors that affect salivary gland tumors, high-dose radiation exposure plays a well-known role. Frequent X-ray examinations, radioactive iodine therapy, and excessive ultraviolet radiation have a negative effect. The effect of radiation was studied in residents of Hiroshima and Nagasaki 13-25 years after the atomic explosion. A higher frequency of benign and malignant salivary gland tumors was noted in this population, especially such as mucoepidermoid carcinoma. Studies conducted to study the causes of lymphoepithelioma showed that 11.4% of patients had previously been exposed to radiation, and in 9.8% of patients, the salivary gland tumor was within the radiation field. Many authors point to the potential risk of ultraviolet radiation. An increase in the incidence of salivary gland tumors has been noted in individuals who had previously received ionizing radiation for various head and neck tumors, including in childhood for dermatomycosis of the head, and in individuals who were treated with radioactive iodine for hyperthyroidism. Frequent X-ray examination of the head and neck organs also contributes to the development of tumors.

Viruses

The reports concerning the role of oncogenic viruses convincingly testify only to the role of the Epstein-Barr virus. The role of cytomegalovirus and human herpes virus has also been studied. In tumors with lymphoid stroma, there is a correlation between the amount of Epstein-Barr virus and undifferentiated carcinoma of the nasopharynx. This ratio was recorded among residents of North America, Greenland and southern China. Lymphoepithelial carcinoma and undifferentiated carcinoma of the salivary glands in these populations had similar pathogenetic connections with the Epstein-Barr virus. The action of the virus consists in the introduction of the product of its vital activity (oncoprotein) into the epithelial neoplastic cells of these tumors. The high frequency of these tumors in Eskimos and southern Chinese is the result of an increase in the oncogenic potential of the virus or genetic susceptibility. The association of undifferentiated parotid carcinoma and the virus in Caucasian patients has also been confirmed. The data on the effect of the virus on the incidence of benign neoplasms have also been confirmed. Under the influence of the virus, changes occur in the epithelial cells of the salivary glands in the form of lymphoepithelial proliferation and inflammatory changes, especially in ductal cells and B-lymphocytes. Salivary gland tumors, especially adenolymphoma, which are characterized by lymphoepithelial proliferation, develop as a result of the virus. In 87% of cases of multiple or bilateral adenolymphomas, the altered genome of the Epstein-Barr virus was found in the cytoplasm of neoplastic oxyphilic cells, compared to solitary adenolymphoma, in which the virus genome was detected in 17% of cases (the Epstein-Barr virus genome was detected in the cytoplasm of ductal cells of bilateral adenolymphomas in 75% of cases, in 33% of cases of solitary adenolymphomas, and a small amount was found in acinar cells. Adenolymphomas are often combined with some autoimmune diseases that lead to the development of infection and a state of immune depression. Studies show a high level of O-antibodies to the capsid and early antigens of the Epstein-Barr virus; the relationship between H1-A-DR6 antigens is also of statistical significance. A significant prevalence of infection caused by the virus is known in the Chinese population with a high frequency of lymphoepitheliomas Epstein-Barr (25% among tumors of the parotid gland). The presented data confirm the role of the Epstein-Barr virus in the pathogenesis of adenolymphoma.

Smoking

The influence of smoking on etiology is confirmed by many authors. For example, Italian and American researchers point to the connection between smoking and adenolymphoma. They note the presence of adenolymphoma in 87% and pleomorphic adenoma in 35% of long-term and heavy smokers. However, smoking does not cause malignant tumors of the salivary gland.

Profession

The influence of some professions on salivary gland tumors has been shown. These are workers in the rubber, metallurgy, woodworking, automobile industries, asbestos mines, chemical laboratories, beauty salons and hairdressers. They are exposed to components of lead, nickel, silicon, chromium, asbestos, and cement dust during the production process.

Nutrition

Potential risk factors for salivary gland tumors include the use of kerosene in cooking, high cholesterol, and low vitamin intake. Low intake of yellow vegetables, fruits, and plant foods has a detrimental effect.

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Hormones

Endogenous hormonal activity has been detected in normal and tumor tissue of the salivary gland. In normal salivary gland tissue, estrogen receptors have been found in 80% of cases in women and men, and in half of cases of salivary gland tumors in women, estrogen expression has been detected, as in hormone-dependent breast cancer. Publications indicate the presence of a small number of estrogen receptors in acinar cell and mucoepidermoid carcinoma; they are found in adenoid cystic carcinoma and are absent in tumors from the ducts of the salivary gland. Progesterone receptors have been detected in normal salivary gland tissue in some pleomorphic adenomas; however, this fact has no prognostic significance. Androgen receptors are found in more than 90% of ductal carcinomas. Androgen receptor immunoreactivity is characteristic of all salivary gland duct cancers, pleomorphic adenoma carcinomas, and basal cell adenocarcinomas. About 20% of mucoepidermoid, acinic cell, and adenoid cystic carcinomas are positive for androgen receptors.

Gene mutations of salivary oncogenes

Cytogenetic and molecular studies of chromosomal and gene mutations in benign and malignant salivary gland tumors conducted in recent years have expanded the possibilities of successful diagnostics, therapy, and prognosis of the tumor process. Specific structural chromosomal changes in various histological types of salivary gland tumors are the result of the movement of genetic material involving chromosome 8 in pleomorphic adenoma, chromosome 11 in mucoepidermoid carcinoma, and translocation on chromosome 6 in adenoid cystic carcinoma.

The most studied of the alternating chromosomes is the Y chromosome in adenocarcinomas. In mucoepidermoid carcinoma of the root of the tongue, the trisomy 5 gene has been described as an abnormal karyotype. Polysomic chromosomes 3 and 17 are significant for adenoid cystic carcinoma; the tumor suppressor gene located on this chromosome is also of interest.

Analysis of genetic abnormalities reveals microsatellite duplication of most chromosomal regions and a situation in which there is an increase in the reaction with the polymerase chain reaction (PCR). This is a sensitive marker that detects replication errors and genomic mutations. There is a loss of the allelic gene in chromosome 12p (35% of cases) and chromosome 19q (40% of cases) in pleomorphic adenoma, adenoid cystic carcinoma. Mucoepidermoid carcinoma shows 50% and a greater loss of 2q, 5p, 1 2p, 16q. Most pleomorphic adenomas lose the allelic gene on chromosome 8, which is observed in 53% of malignant and 41% of benign tumors. Malignant tumors that have lost the heterozygous gene acquire aggressive properties, and the transformation of benign pleomorphic adenoma into a malignant tumor is associated with changes on the surface of chromosome 17.

Thus, loss of the allele gene and heterozygous gene (LOH) causes changes in chromosomes 1 2p and 19q in mucoepidermoid carcinoma, chromosome 8 in adenoid cystic carcinoma and LOH in many chromosomal zones of malignant tumors, which confirms the importance of genetic changes in tumor genesis for the salivary glands. Modern studies have made it possible to isolate genes that involve the salivary glands in the tumor process. Oncogenes are activated and suppressor genes are inactivated.

The best known tumor suppressor gene p53 is located on chromosome 17 (p13) and is frequently detected in some benign and especially in malignant tumors of the salivary gland. The mutation product of the p53 gene accumulates in the nucleus of the neoplastic cell and was found in 3 (11%) of 26 benign and in 31 (67%) of 46 malignant tumors of the parotid salivary gland. Reports indicate that p53 aberrations were associated with regional and distant metastases. Mutations in p53 and/or p53 protein expression are present in most salivary gland tumors, including adenoid cystic carcinomas, salivary duct adenocarcinomas and carcinomas, pleomorphic adenomas and carcinomas, as well as in mucoepidermoid and squamous cell carcinomas. Transformation of GC cells into tumor cells occurs. Increased p53 expression affects factors promoting angiogenesis. Absence or decrease in E-cadherin expression is a sensitive prognostic marker for adenoid cystic carcinoma, confirming the role of tumor suppression of the gene.

The study of oncogenes c-erbB-2 (HER-2, pei) confirms the analogy existing between salivary gland tumors and breast tumors. Increased protooncogenes, complexity of their structure, expression of their proteins were detected in 35% of patients with salivary gland tumors and correlated with tumor aggressiveness, especially in adenoid cystic carcinomas and adenocarcinomas of large SG. Overexpression of c-erb-B2 is detected in 47% of Warthin tumors and in 33% of pleomorphic adenomas.

Expression of the proto-oncogene C-Kit encoding a transmembrane type of tyrosine kinase receptor was detected in adenoid cystic and myoepithelial cancers of the GS and was absent in other morphological types of carcinomas. None of the tumors expressing this gene had gene mutations in exons 11 and 17. The results of the studies emphasize the possible important role of gene activation mechanisms and other genetic disorders. Further studies of this gene revealed its high expression in some other salivary gland tumors (including monomorphic types of adenomas). 

Salivary gland tumors: types

Salivary gland tumors are a diverse and complex group of tumors, so their classification is difficult. Morphological signs of malignancy are not always reflected in the clinical manifestation of the neoplasm. It is almost impossible to express the clinical and morphological features of each nosological unit and present them in a single classification. That is why salivary gland tumors studied by pathologists have been improved as modern data accumulated and were formalized into an international histological classification adopted by WHO in 1972, which was supplemented and approved by WHO in 1991. However, this does not mean that the pathomorphology of tumors has been studied thoroughly. Modern ultrastructural studies help not only to imagine the morphological nature of the tumor, but also to determine the degree of malignancy and the response to treatment.

The classification used by domestic oncologists included three groups of tumors:

1. Benign tumor of the salivary gland:
   • epithelial (adenoma, adenolymphoma, mixed tumor);
   • connective tissue (fibroma, hemangioma, chondroma, etc.);
2. Locally destructive tumor of the salivary gland:
   • mucoepidermoid tumor, cylindroma.
3. Malignant tumor of the salivary gland:
   • epithelial (cancer);
   • connective tissue (sarcoma, etc.);
   • malignant, developed from benign neoplasms;
   • secondary (metastatic).

What is the prognosis for a salivary gland tumor?

The main prognostic and predictive factors are those that influence survival. They include morphological criteria (histological type and degree of tumor malignancy), etiology, localization, prevalence of the tumor process, and methods of therapeutic intervention. The study of objective criteria for assessing the effectiveness of treatment allows predicting the outcome of the disease. The most important of these criteria are the frequency of relapses and metastases. The most pronounced correlation is the prognosis with the clinical stage of the tumor process, which emphasizes the importance of making a diagnosis as early as possible. It has been shown that the microscopic degree of differentiation ("grade") and the tumor type are independent prognostic factors and often play a major role in optimizing the treatment process. The tendency of many neoplasms to relapse, regional and distant metastasis indicates the need in many cases to resort to more aggressive initial treatment tactics. The relationship between the clinical stage of the disease and the degree of differentiation ("grade") of the tumor indicates the biological feature of the tumor, allows predicting the stages of disease development (clinical course) and the response to the methods of treatment. The influence of prognostic factors for each morphological type of tumor has its own characteristics. A benign tumor of the salivary gland has an adequate surgical intervention as the main factor determining the prognosis. However, the biological feature of some tumors is manifested by a tendency to relapse and malignancy. Thus, a salivary gland tumor, basal cell adenoma, usually does not relapse, with the exception of the membranous type, which reoccurs in about 25% of cases. There are reports of malignant transformation of basal cell adenoma, although this is extremely rare. Relapses after surgical treatment (parotidectomy or enucleation) occur in 2-2.5% of cases, which is mainly due to the multifocal nature of tumor growth. Regarding prognostic and predictive factors in relation to adenolymphoma, it should be said that malignancy of adenolymphoma is rare - about 1% of observations. Malignancy may concern the epithelial or lymphoid component. Some patients have a history of exposure to radiation. Adenolymphoma sometimes occurs in combination with other benign tumors of the salivary gland, especially often with pleomorphic adenoma. There are studies indicating an increase in the frequency of "extrasalivar" tumors in adenolymphoma. Here, smoking probably explains the common etiology for adenolymphoma and cancer of the lung, larynx, bladder, while other neoplasms (kidney cancer, breast cancer, etc.) apparently represent a random combination.

For adenoid cystic carcinoma, the histological type, tumor localization, clinical stage, presence of bone lesions, and the state of surgical resection margins are decisive. In general, tumors consisting of cribriform and tubular structures have a less aggressive course than those with solid areas occupying 30% or more of the tumor area. The clinical stage of the disease has a significant impact on the prognosis. In other studies, attempts to confirm the prognostic value of the "grade" failed, and the prognostic value of the clinical stage and tumor size as the most constant factors of clinical outcome in these patients was revised. Five-year survival is 35%, but more remote results are significantly worse. From 80 to 90% of patients die after 10-15 years. Local relapses, according to various data, occur in 16-85% of cases. Relapse is a serious sign of incurability. Lymph node involvement is uncommon, ranging from 5% to 25%, usually occurring in tumors located in the submandibular SG, due to direct extension to a lymph node rather than metastasis. Distant metastases occur in 25% to 55% of adenoid cystic carcinomas; the most common sites of metastasis are the lungs, bones, brain, and liver. Only 20% of patients with distant metastases survive 5 years or more. The effect of perineural invasion on survival is controversial. Wide radical local excision followed by radiation therapy is the treatment of choice. Radiation therapy alone or in combination with chemotherapy has limited success in the treatment of relapses or metastatic disease but does improve outcomes when used locally to control microscopically residual disease. The value of chemotherapy in acinar cell carcinoma is limited and requires further study.