Introduction
There was a paradigm shift in the understanding of the pathogenesis of sialoliths, also known as salivary calculi, at the turn of the century. This was the result of experimental and clinicopathologic investigations that led to the discovery that sialolithiasis (the presence of a sialolith) was secondary to chronic sialadenitis. Rediscovery, however, would be more appropriate, because this conclusion had been reached in 1896 by Küttner, who described his clinical and microscopic investigations of two patients each with a swollen submandibular gland that had originally attracted a diagnosis of malignancy. He realized that the swellings were caused by chronic inflammation that, together with fibrosis, had led to the clinical appearance of malignancy ( Fig. 10.1 ). He found a sialolith the size of a cherrystone in the gland of one of the patients, who had complained of a submandibular swelling for 10 years. He considered that the sialolith was secondary to the inflammation because the sialolith was far too small for a concretion of 10 years’ accumulation, and because of the absence of a sialolith in the other case, in which the duration was only 1.5 months. Küttner’s opinion that chronic sialadenitis is primary and leads to the formation of a sialolith was confirmed by extensive clinical experience ( Fig. 10.2 ).
However, there was negligible appreciation of Küttner’s work in the English-language medical literature, in which the notion that the sialolith is primary and the chronic sialadenitis is secondary held sway, although there was no evidence to account for the formation of the sialolith.
Clinicopathologic Investigations
One of the clinicopathologic investigations that led to the paradigm shift and the rediscovery that sialolithiasis is secondary to chronic sialadenitis involved 154 cases of chronic submandibular sialadenitis, in which 18 different clinical and histologic features were statistically analyzed. It revealed that there is a chronological progression of increasingly severe chronic sialadenitis with, in many cases, the eventual development of a sialolith.
The search for possible pathogenic factors that could transform a normal gland into a diseased gland led to a postmortem investigation in which microscopic concretions, called sialomicroliths, were found in all normal submandibular glands and 20% of normal parotids. This distribution relates to a higher concentration of ionic calcium in the submandibular gland. Ionic calcium is present to shield the anionic charges of molecules of acidic secretory material and thus to allow them to be condensed into secretory granules. The concentration of calcium thus corresponds to the acidity of the secretory material in the secretory granules. (More details are given in Chapter 5 .)
The realization of the extent of the occurrence of sialomicroliths was only achieved through electronmicroscopy ( Fig. 10.3 ), because many sialomicroliths are indistinguishable from secretory granules lightmicroscopically or are below the level of lightmicroscopic resolution.
Sialomicroliths were occasionally seen obstructing small intraglandular ducts and causing focal obstructive atrophy ( Fig. 10.4 ). This led to the hypothesis that sialomicroliths impact in ducts and accrete to form sialoliths, which led to a search for sialomicroliths in cases of chronic submandibular sialadenitis. They were found in all cases, which appeared to support the hypothesis. However, no relation between sialomicroliths and sialoliths or between sialomicroliths and duration of symptoms in chronic submandibular sialadenitis could be found. This indicated that sialomicroliths are not incipient sialoliths.
Experimental Investigations
The search for pathogenic factors was finally resolved by experimental investigations using rat, cat, and ferret.
Sialomicroliths and chronic obstructive sialadenitis were produced in the parotid and submandibular gland of rats made hypercalcemic and given repeated high doses of isoprenaline. Isoprenaline given in repeated high doses produces a great increase in the size and weight of the parotid and submandibular gland of rat as a result of hyperplasia and hypertrophy of the acinar cells. The acinar enlargement is sufficient to result in compression of the intraglandular ducts. Every dose of isoprenaline is followed by an explosive release of secretory material from the acinar cells that is unable to flow freely through the lumina of the compressed ducts, and the resultant increase of luminal pressure damages acinar cells. The partial obstruction thus results in a mixture of stagnant secretory material, which is particularly rich in calcium because of the hypercalcemia, and cellular debris. Cellular membranes present in the debris contain phospholipid that is exposed when they are damaged. This exposed phospholipid is a potent nucleator of calcification. The combination of stagnant calcium-rich secretory material together with phospholipid allows the calcium to precipitate on the phospholipid to form sialomicroliths. This occurs in the small intraglandular ducts and the sialomicroliths can obstruct them to give rise to chronic obstructive sialadenitis ( Fig. 10.5 ).
The salivary glands of cat were found to be a particularly valuable experimental model. Parasympathectomy caused a greatly increased occurrence of sialomicroliths in submandibular glands, in which they were extensively present in most of the parasympathectomized glands. This led to the realization that the lack of parasympathetic secretory stimulation caused a pathologic accumulation of sialomicroliths ( Fig. 10.6 ). The acinar secretory granules of the submandibular gland of cat contain a high level of sequestered ionic calcium associated with acidic secretory material. The sequestered calcium is released in an ionized form during the normal discharge of secretory granules from the cell or during the degradation of secretory granules in autophagosomes when there is secretory inactivity, such as caused by parasympathectomy. The phospholipid of cellular membranes becomes exposed during degradation in autophagosomes and the ionic calcium precipitates on the phospholipid to form calcified sialomicroliths. This saves the cell from toxic death owing to an overwhelming sudden release of ionic calcium. Sialomicroliths may be expelled from cells and pass into lumina. They may also be formed in stagnant secretory material in lumina ( Fig. 10.7 ). Luminal sialomicroliths may be flushed away in the saliva, although if they impact in a small intraglandular duct, a focus of obstructive atrophy may be produced. This is more likely to occur when a pathologic accumulation of sialomicroliths occurs, such as when there is secretory inactivity.
The parotid of ferret frequently contains sialomicroliths. Secretory inactivity causes stagnation and autophagy of calcium-rich secretory material, which leads to the production of sialomicroliths that can obstruct small intraglandular ducts and produce atrophic foci.
Investigations on ductal ligation of the salivary glands of cat yielded information on obstructive atrophy and recovery. The parotid is the most susceptible to obstruction, with progressive atrophy; the submandibular gland is more resistant, with variable atrophy; and the sublingual gland is the most resistant, with not only variable atrophy but extravasation of mucus that sometimes forms an extravasation mucocele. The parenchyma of obstructed glands can adapt and survive, and obstructed glands are capable of recovery, which depends on the duration and degree of obstruction. Complete obstruction does not lead to an accumulation of sialomicroliths or produce sialoliths.
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