44 Salivary Gland Regeneration and Tissue Engineering

Introduction

Epidemiology and Etiology of Salivary Gland Hypofunction

Morphology and Mechanisms of Postradiotherapy Salivary Gland Hypofunction

Morphological Aspects

Mechanisms of Radiation-Induced Salivary Gland Damage

Current Treatment Modalities for Xerostomia

Radiation Damage

Amifostine

Other Options

Experimental Treatments

Tissue Engineering

Gene Therapy–Based Strategies

Stem Cell–Based Salivary Gland Regeneration

Future Trends

Key Points

Introduction

Treatment options are currently very limited, independently of the underlying reason for salivary gland hypofunction. Only in Sjögren disease is there a potential treatment option, by administering an anti-CD20 antibody directed against the etiological B cells that have infiltrated the salivary gland parenchyma.¹ In radiation-induced salivary gland hypofunction, prophylactic treatments to prevent and reduce xerostomia are frequently used and are often combined with symptomatic therapies. In spite of these and many other measures discussed in this chapter, xerostomia is an unresolved problem in modern otorhinolaryngology and oral medicine for which an urgent solution is being sought. It may be possible to solve it by using novel therapeutic strategies, and these are explained and discussed here.

Epidemiology and Etiology of Salivary Gland Hypofunction

Salivary gland hypofunction is frequently a consequence of treatments administered (radiotherapy) or prescribed (radioiodine or medications) for a variety of diseases (for further details, see Chapter 14). Sjögren disease and other immunological disorders, including graft-versus-host disease and human immunodeficiency virus (HIV) infection, can also result in gland hypofunction (for more details on these specific diseases, see Chapter 16). There are also a significant number of patients with symptoms of xerostomia in whom a specific cause is not identified, who are classified as having idiopathic xerostomia. Overall, the prevalence of xerostomia is unknown, mainly due to the lack of definitions and appropriate studies. In a review of the available data, Orellana et al. concluded that the prevalence of xerostomia is in the range of 0.9%–64.8%; the majority of such studies have been conducted in Scandinavia.² More than 300 000–500 000 patients throughout the world undergo radiotherapy for head and neck cancer each year,³ and the majority of these patients are likely to develop severe salivary gland hypofunction. Xerostomia is thus clearly an enormous health problem that has a severe impact on patients’ quality of life.

Morphology and Mechanisms of Postradiotherapy Salivary Gland Hypofunction

Morphological Aspects

Both the therapeutic effects and side effects of radiotherapy result from many different factors, including the total dose, the overall fractionation scheme, and the dose per fraction used. The different phases of tissue damage have been characterized and reported in detail in experiments on rat submandibular and parotid glands. Four typical phases⁴ have been characterized:

Phase I is the early phase of damage, starting immediately after radiation and lasting about 10 days. During this period, water secretion is reduced by about 40% of the nonirradiated control glands. A change in amylase secretion or loss of cells does not take place until the tenth day.

During phase II, about 10–60 days after radiation, acinar cells decrease in number, as well as amylase production.

In phase III, between 60 and 120 days, no additional cellular changes are noted.

In phase IV, between days 120 and 240, chronic salivary gland damage becomes apparent. This phase is characterized by a loss of regenerating acinar cells and a decrease in the salivary flow rate and amylase production.

Seifert et al.⁵ characterized similar effects of radiation damage in the human salivary glands. They described three different phases of damage:

During the initial phase, the gland becomes swollen and vacuolar.

In the intermediate stage, atrophic glandular acini, dilated ducts, and fibrosis become evident.

In the terminal stage (phase III), the acini are destroyed, and dilated ducts and mucous granuloma are identified.

There is experimental evidence from rat models and clinical evidence in humans that serous acini are more susceptible to radiation damage than mucous acini.⁵ This explains the observation that the mainly serous parotid gland is more susceptible to radiation injury than the submandibular and minor salivary glands, which are predominantly mucous in function.

Mechanisms of Radiation-Induced Salivary Gland Damage

The mechanisms of radiation damage are not fully understood (see also Chapter 42 on protection during radiotherapy).⁶ However, some aspects have been investigated. The higher susceptibility of serous acinar cells is explained by the production of free radicals of metal ions, such as copper, iron, and zinc, which are part of the composition of the secretory proteins of the serous acinar cells. On the other hand, radiation damage to local blood vessels, nerves, and the local tissue stroma can enhance these effects, resulting in salivary gland hypofunction. The effect of radiation on acinar cells⁶ is more important than its effect on ductal epithelial cells, as the acinar cells’ main contributory function is in water production and creating most of the organic secretory proteins in saliva,⁷ while the ductal cells are “only” responsible for modifying and excreting the saliva.

The limited regeneration capacity of acinar cells after radiotherapy is probably the result of them undergoing repeated mitosis in an effort to combat the effects of radiation damage. These radiation-induced repeated mitoses significantly reduce the acinar cells’ proliferative capacity following radiotherapy. Secondary DNA damage and chromosome impairment in vital cells^4,7 further add to these effects. Experimental data from rats suggest that proliferation of the different cells is significantly increased following each individual dose of radiation.⁸ Recent studies have supported this hypothesis and the view that the process of acinar cell loss is caused by p53-dependent apoptosis.⁹

In summary, current findings suggest that the mechanisms of postradiation salivary gland hypofunction are due to loss of the acinar cells, leading to a loss of salivary function. Using tissue engineering techniques to generate acinar cells or acini as a whole-tissue complexes might therefore be one possible way of restoring salivary function. Other options available include the use of gene therapy approaches, which attempt to transmit the lost function of acinar cells to other local cells that have survived radiotherapy. Finally, using stem cells to replace and regenerate the functional cells, as well as some of the neural, vascular, and stromal tissue components might also be a reasonable alternative option.¹⁰ These different approaches are currently undergoing experimental, preclinical, and clinical research investigations.

Current Treatment Modalities for Xerostomia

As mentioned, the treatment options for salivary gland hypofunction—with its well-known sequelae of dental caries, dysphagia, dysarthria, and oral cavity infection—are currently limited to symptomatic therapies.

The only exception is Sjögren syndrome, an immunological disease involving progressive parenchymal atrophy and the formation of lymphoepithelial lesions in striated ducts, resulting in xerostomia (for more details, see Chapter 16). Treatment with rituximab, an antibody directed against CD20, has been used for non-Hodgkin lymphoma and other autoimmune disorders for many years, and in an uncontrolled trial this recently demonstrated benefit in patients with Sjögren syndrome.¹ By reducing the causative lymphoepithelial lesions, rituximab treatment led to improved salivary composition and flow, with relief from the clinical symptoms of xerostomia for the patients. These findings are currently awaiting confirmation in a randomized trial.1

Radiation Damage

One treatment option is to reduce radiation damage through preventive measures. Intensity-modulated radiation therapy (IMRT), a relatively new technique, is able to reduce the radiation dose to adjacent tissues, such as the salivary glands, in comparison with the standard use of external-beam radiotherapy techniques, while at the same time minimizing the severity of xerostomia.¹¹ IMRT can of course only be administered when the disease is in a suitable anatomic location—tumors located in the salivary glands, oral cavity, and oropharynx. In many cases, one parotid gland can be spared—minimizing the effects on salivary tissue and resulting in a smaller reduction in salivary flow.

This technique is not yet available in all cancer centers in Europe. In addition, reducing the radiation exposure to the parotid glands may not be sufficient to prevent patients from the sequelae of radiation damage, as the submandibular glands and minor salivary glands are not spared with this technique.¹²

Amifostine

Another option is to reduce radiation damage by administering substances such as amifostine. Amifostine is a commercially available thiophosphate derivative that is used for cytoprotection in radiotherapy and chemotherapy. The substance is clearly more active in healthy cells than in tumor cells. It disables free radicals and complexes active platinum derivatives, thus protecting normal cells from therapy-induced DNA damage. This treatment has been investigated in a variety of clinical trials using different study protocols and reporting varying results. A recent Cochrane analysis has reported that there is no good evidence that the use of amifostine in patients treated with radioiodine for thyroid cancer has any beneficial effect.¹³ Its lack of effectiveness in preventing xerostomia when administered to patients undergoing conventional external-beam radiotherapy has also led to its use being abandoned in most cancer centers worldwide.

Other Options

Other options include surgical transfer of the submandibular glands outside of the radiation field, most often to the submental area.¹⁴ Symptomatic treatment using pilocarpine requires the presence of some remaining functional salivary tissue capable of being stimulated. In many cases, however, only a limited effect of treatment can be observed, and pilocarpine is contraindicated if the patient has asthma. In addition, it may induce several side effects such as palpitation and sweating. Administration of saliva substitutes or “artificial saliva” is yet another option that may provide some relief, although patients find that the substitutes are not very helpful, as their effect is only short-lived.

Experimental Treatments

The lack of effective and causative therapies has led to the development of many different experimental strategies, including tissue engineering, gene therapy, and stem cell–based treatments, discussed below.

The efficacy of other recently proposed treatment regimens such as acupuncture and laser phototherapy has yet to be proved in randomized trials. Traditional Chinese medicine, in which there is long experience in the treatment of xerostomia, also still requires verification in appropriate clinical studies. The effects of Chinese herbs have recently been studied in vitro in rat submandibular gland cells, and the results have shown that there is some increased fluid secretion when certain combinations are used. More recently, it has been proposed that autotransplantation of cryopreserved minor salivary glands may be an alternative treatment (see Chapter 43).

Another interesting new form of medicinal treatment that has been proposed is administration of botulinum toxin to reduce postradiotherapy hypofunction. However, the treatment has only been tested once in a small cohort in a rat study.¹⁵ The treatment is a particularly novel one, as the reduction in saliva flow during radiotherapy in this experimental model contrasts with clinical practice and experimental evidence.¹⁶ In clinical practice, patients are encouraged to stimulate saliva flow using pilocarpine or drops and chewing gum during radiotherapy. The authors, who argue in favor of reducing salivary flow during radiotherapy, hypothesize that the formation of toxic granules inside the secretory cells can be reduced by reducing saliva production.¹⁵ However, this hypothesis has yet to be confirmed with stronger evidence in further experimental work, as well as clinical trials. The evidence of an increased mitotic rate during radiotherapy as the main cause of radiogenic xerostomia⁷ would be an argument against increasing salivary flow by stimulating increased acinar cell proliferation, favoring salivary gland immobilization with botulinum toxin rather than stimulation with pilocarpine. Table 44.1 provides an overview of experimental therapies.

VEGF, vascular endothelial growth factor.

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