The principal site of iodide transport into saliva is the epithelium of the salivary glands’ intralobular ducts.^8,13 Iodide is extracted from the periductal capillaries, is concentrated by the ductal epithelium, and is secreted into the ductal lumen and then into the oral cavity. Approximately 24 percent of the ¹³¹I administered is lost in the saliva.⁹

Immediately after receiving a dose of ¹³¹I, some patients have experienced transient swelling and decreased salivary flow; the condition usually is bilateral and involves the parotid glands.^12,14–18 Radiation damage causes a glandular inflammatory infiltrate and concomitant swelling, which can lead to an increase in periductal pressure and ductal constriction. Salivary retention develops and adds to the swelling and pain originating from the initial radioactive effect on the salivary gland. The effect is rapid and obviously dose-related, but resolution of the inflammation and its symptoms usually occurs within a few days.^{11,14–17,19}

Because the swellings are transient, it was assumed that patients would encounter no further objective and subjective symptomatology. Reports of permanent harm have appeared, however.^3,20–22 Longer elapsed posttreatment time frames or additional ¹³¹I treatments have allowed for continued progression of gland damage, as the effects of the ionizing radiation incorporated into the cell’s genetic structure appear in succeeding cell generations.

In the months after ¹³¹I treatment, many patients complain of obstructive parotitis that may be unilateral or bilateral. Less frequently, the patients’ complaints involve the submandibular salivary gland. The obstructive symptoms—swelling and pain—develop owing to salivary retention. Inflammation of the ductal wall and shedding of inflammatory debris into the ductal lumen combine to narrow the lumen, obstruct salivary flow and cause swelling. When patients eat, the symptoms are accentuated, particularly in the parotid glands, in which the secretions increase and are retained. Continued exacerbations can cause further damage to the gland.¹⁸

Salivary hypofunction usually is not a primary patient complaint. Oral dryness is contingent on the extent of the parenchymal damage generated by the radioiodine dosage and the passage of time. Parotid gland secretion usually is reduced by about 40 percent after doses of 270 mCi of ¹³¹I^23,24 and by 50 to 60 percent in those who receive 500 mCi of ¹³¹I,^24,25 and it approaches 100 percent in those who receive 1 curie of ¹³¹I or more.^20,24,25 Oral dryness is an infrequent complaint when patients receive a therapeutic ¹³¹I dose ranging from 100 to 200 mCi. Higher doses can cause uniform and significant parenchymal cell damage with associated salivary hypofunction. Furthermore, because the effects of the irradiation are asymmetric, some salivary glands can remain clinically unaffected and continue to produce normal salivary volumes.

Practitioners should be aware of whether their patients have received ¹³¹I therapy and subsequently complain of sialadenitis. The following two case reports illustrate the diverse characteristics of ¹³¹I-induced radiation sialadenitis.

	CASE REPORTS

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Case 1. A 55-year-old woman was first seen in October 2005 in the Salivary Gland Center (SGC) at Columbia University College of Dental Medicine in New York City after having experienced sporadic left parotid gland swellings for two months in association with eating.

In September 2004, she had had her thyroid gland removed surgically owing to the presence of a papillary thyroid carcinoma. In January 2005, she received 150 mCi of ¹³¹I to control therapeutically any residual malignancy. No glandular swellings developed in the period immediately after the administration of ¹³¹I.

At the time we examined her at the SGC, her left parotid gland was slightly swollen but we found no other salivary gland swelling. When we digitally palpated the glands, we found that the left parotid gland was somewhat firm and tender, while the other salivary glands were asymptomatic. When we applied manual pressure to the right parotid gland and both submandibular glands, we noted normal salivary flows. When we aggressively massaged the left parotid gland, however, no saliva could be expressed through its duct orifice.

To ascertain the real-time activity of the salivary glands, we performed a radioisotope study with technetium Tc 99m pertechnetate (TPT). A real-time/activity graph indicated that the left parotid gland failed to trap and secrete the TPT adequately (Figure 1A). The right parotid gland and the two submandibular glands demonstrated normal uptake and release of the TPT (Figures 1A and 1B, respectively).

View larger version (70K): [in this window] [in a new window]   Figure 1. Case 1. A. Parotid gland time/activity graph demonstrates normal uptake of technetium Tc 99m pertechnetate (TPT) by the right parotid gland (R) with normal secretion of the radioisotope at the 10-minute mark. The left parotid gland (L) failed to concentrate and secrete TPT adequately. B. Submandibular gland time/activity graph demonstrates normal uptake and secretion of TPT by the right (R) and left (L) submandibular salivary glands.

In March 2004, she underwent a partial thyroidectomy, owing to the presence of a papillary thyroid carcinoma. In May 2004, she received 30 mCi of ¹³¹I. In November 2004, she received another 150 mCi of ¹³¹I. In September 2005, she underwent surgery to remove thyroid remnants and any residual tumor tissue.

When we examined the patient, none of her salivary glands were swollen. When we digitally palpated the salivary glands, we found that both submandibular salivary glands were tender and firm, while the parotid glands were painless and normal in tone. We noted that saliva flowed freely from the orifices of both parotid gland ducts. We saw no saliva exiting from the right or the left submandibular duct orifices despite applying external pressure to them.

A real-time/activity graph depicting the uptake and secretion of TPT by the salivary glands showed normal activity of the parotid glands, although the activity of the right parotid gland lagged slightly behind that of the left parotid gland (Figure 2A). Conversely, the submandibular salivary glands minimally trapped the TPT and failed to secrete the radioisotope at the 10-minute mark (Figure 2B). This confirmed the clinical finding of essentially normal parotid gland secretions with the absence of submandibular gland secretions.

View larger version (67K): [in this window] [in a new window]   Figure 2. Case 2. A. Parotid gland time/activity graph demonstrates that both parotid glands show normal technetium Tc 99m pertechnetate (TPT) uptake followed by normal secretion of the radioisotope at the 10-minute mark. The right parotid (R) gland activity lags slightly behind that of the left parotid (L) gland. B. Submandibular gland time/activity graph demonstrates inadequate uptake and failure to secrete TPT by both the right (R) and left (L) submandibular glands.

	DISCUSSION

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At the SGC, we evaluate patients who have ¹³¹I-induced salivary gland dysfunction via a scintigraphic examination that uses intravenously introduced TPT. TPT is a radioisotope of molybdenum with a six-hour half-life. It emits nondestructive gamma radiation rather than the destructive beta radiation, which is emitted by ¹³¹I. After it is introduced intravenously, TPT is concentrated effectively by the salivary gland’s parenchymal tissue, is imaged digitally by a gamma camera, and is plotted on a time/activity graph over a 10-minute span. After 10 minutes, the patient sucks on a sour candy to stimulate secretory activity, which also is imaged and plotted for 10 minutes.

Scintigraphic imaging has significant advantages over sialography in that it allows clinicians to visualize the 20-minute real-time activity of four glands—two parotid glands and two submandibular glands—simultaneously. It also allows parenchymal and ductal functions to be depicted graphically. Sialography images only the ductal structure of one gland at one point in time.

The effects of ¹³¹I on the excretory ducts and on the parenchyma are independent of each other. Initially, TPT uptake may be normal, but because of damage to the duct wall, TPT clearance may be delayed and retention may occur. Later, diminished TPT trapping may occur owing to a slowly developing vascular fibrosis resulting from the destructive effect of ¹³¹I.

Because the dose-dependent effect of radioiodine is delayed, salivary secretion tends to decrease slowly with time.^24–27 The dysfunction that develops can be mild to severe, asymmetric and even subjectively asymptomatic.

The patient in our first case report developed problems with her left parotid gland seven months after receiving a moderately high (150 mCi) dose of ¹³¹I. The left parotid gland was damaged clinically, as evidenced by its ineffective trapping and secretion of the TPT (Figure 1A). The right parotid gland activity was within normal limits. Neither of the submandibular glands had evidence of damage, revealing the decreased vulnerability of these glands to the effects of ¹³¹I (Figure 1B). However, because our study was conducted only seven months after therapy, the patient may experience further degenerative gland changes in the future.

We also observed the asymmetric salivary gland experience with radioactive iodine in the patient in our second case report. Despite a 22-month and 16-month lapse after receiving 30 mCi and 150 mCi of ¹³¹I, respectively, the patient’s parotid glands essentially were normal (Figure 2A), while both submandibular glands were conspicuously injured (Figure 2B).

The flatlining we observed on the submandibular gland time/activity graph (Figure 2B) reflected the gland’s inability to adequately concentrate and a failure to secrete the TPT radioisotope. This is surprising in view of the fact that the mucous cells of the submandibular glands tend to trap less iodide and to be more resistant to radiation than do the parotid glands, which apparently were not affected. Regardless, the normal function of the parotid glands in the future is in doubt. Salivary hypofunction with resultant caries and subjective xerostomic complaints have not become an issue in either of our patients. In both cases, salivary production from glands that have not been injured significantly because greater doses were not used has avoided the problems that accompany hypofunction. Regardless, the symptom complex associated with oral dryness may develop with time and requires the patients to be monitored.

Radiation damage to the salivary glands is irreversible, and there is no completely satisfactory therapy available. Treatment of a swollen and painful gland is directed at achieving patient comfort. Aggressive external massage of the affected gland is advised to milk out retained saliva, increase salivary lavage and flush out duct debris. Duct probing may help break up blockages. Nahlieli and Nazarian²⁸ have advocated using endoscopic techniques to irrigate the duct and clear blockages and strictures; in the SGC, we have had some success with irrigating the ducts with dexamethasone. Clinicians may prescribe antibiotics if the patient develops an infection that becomes superimposed on the radiation sialadenitis. Home care must be continuous and include good oral hygiene and use of sialogogic agents such as sugarless gum or sour candy. Daily fluid intake must be maintained to avoid dehydration, which can lead to decreased salivary lavage and recurrent exacerbations.

Salivary hypofunction with oral dryness and discomfort can develop in patients treated with ¹³¹I therapy. Its manifestations are related directly to the radioiodine dosage and the interval since the radioactive iodine was administered. Frequently, there is sufficient functioning gland parenchyma to respond to sugarless sour candy or chewing gum, unlike what occurs after the administration of external beam radiation. Clinicians can prescribe cholinergic agents such as pilocarpine²⁹ or cevimeline³⁰ when the dryness is severe.

	CONCLUSIONS

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Radioactive iodine is an effective treatment for differentiated thyroid carcinomas. Because a significant portion of the administered ¹³¹I is secreted through the salivary glands, a radiation sialadenitis develops.

The effect on the parotid and submandibular salivary glands is asymmetric and manifests itself as an obstructive sialadenitis, decreased salivation or both. The symptoms that develop are in direct proportion to the dosage level of ¹³¹I and the passage of time.

Therapy is limited to caring for the symptoms and aimed at alleviating patients’ discomfort.