Учебники / Textbook and Color Atlas of Salivary Gland Pathology - DIAGNOSIS AND MANAGEMENT Carlson 2008

126 Sialolithiasis

Figure 5.17c. A fi nger was inserted in the oral cavity to	Figure 5.17d. A primary closure was obtained. Reprinted
create better access to the duct, thereby permitting stone	with permission from Ord RA. 2000. Salivary gland disease.
retrieval.	In: Fonseca R (ed.), Oral and Maxillofacial Surgery, Volume
	5, Surgical Pathology. Philadelphia: W.B. Saunders Co.,
	pp. 273–293.

Miscellaneous Sialolithiasis

The incidence of sialolithiasis of the sublingual gland and the minor salivary glands is very rare. In McGurk, Escudier, and Brown’s (2004) study of 455 cases of salivary calculi, no cases were present in the sublingual gland or minor salivary glands. As such, swellings of these glands are most likely to engender a clinical diagnosis of neoplastic disease, with the diagnosis of sialolithiasis made only after final histopathologic analysis of the gland occurs (Figure 5.18). One report examining sialolithiasis of the minor salivary glands found that only 20% of cases were correctly clinically diagnosed as sialolithiasis (Anneroth and Hansen 1983). The paucity of accurate diagnosis may also stem from the frequent spontaneous resolution of

the problem due to ejection of the calculus (Lagha, Alantar, and Samson et al. 2005). Two stages of minor salivary gland sialolithiasis have been described, including an acute stage characterized by inflamed overlying soft tissue whereby the most common clinical diagnosis is cellulitis of the soft tissue. The chronic stage follows and calls to mind a differential diagnosis of neoplasm, irritation fibroma, or foreign body. An anatomic distribution of 126 cases of sialolithiasis of the minor salivary glands identified a significant majority occurring in either the upper lip or the buccal mucosa. As such, sialolithiasis should be included on the differential diagnosis of an indurated submucosal nodule of the upper lip or buccal mucosa, and surgical excision should be performed.

Figure 5.18a. Floor of the mouth swelling present in a 55-year-old woman. Reprinted from: Berry BL. Sialadenitis and sialolithiasis. Diagnosis and management. In: The Comprehensive Management of Salivary Gland Pathology, Carlson ER (ed), Oral and Maxillofacial Surgery Clinics of North America, WB Saunders, Philadelphia, 479–503.

Figure 5.18c. The specimen exhibited mild induration without signs of ranula, such that a neoplastic process was favored while the possibility of a mucous escape reaction was discarded. Reprinted from: Berry BL. Sialadenitis and sialolithiasis. Diagnosis and management. In: The Comprehensive Management of Salivary Gland Pathology, Carlson ER (ed), Oral and Maxillofacial Surgery Clinics of North America, WB Saunders, Philadelphia, 479–503.

d

Figure 5.18b. A diffuse mass is noted beneath the surface mucosa that is smooth and of normal color. A presumptive e diagnosis of ranula vs. neoplasm was established. A left sublingual gland excision was performed in the standard fashion. Reprinted from: Berry BL. Sialadenitis and sialolithiasis. Diagnosis and management. In: The Comprehensive Management of Salivary Gland Pathology, Carlson ER (ed), Oral and Maxillofacial Surgery Clinics of North America, WB Saunders, Philadelphia, 479–503.

Figures 5.18d and 5.18e. Final histopathology showed a sialolith (d) in the background of sialadenitis (e). Reprinted from: Berry BL. Sialadenitis and sialolithiasis. Diagnosis and management. In: The Comprehensive Management of Salivary Gland Pathology, Carlson ER (ed), Oral and Maxillofacial Surgery Clinics of North America, WB Saunders, Philadelphia, 479–503.

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Figure 5.18f. The tissue bed is noted, particularly the lingual nerve (retracted with the vessel loop) and Wharton’s duct. Reprinted from: Berry BL. Sialadenitis and sialolithiasis. Diagnosis and management. In: The Comprehensive Management of Salivary Gland Pathology, Carlson ER (ed), Oral and Maxillofacial Surgery Clinics of North America, WB Saunders, Philadelphia, 479–503.

Figure 5.18g. A 6-month postoperative evaluation showed acceptable healing. Reprinted from: Berry BL. Sialadenitis and sialolithiasis. Diagnosis and management. In: The Comprehensive Management of Salivary Gland Pathology, Carlson ER (ed), Oral and Maxillofacial Surgery Clinics of North America, WB Saunders, Philadelphia, 479–503.

Summary

•Sialoliths are calcium phosphate stones that develop within the ductal system of salivary glands.

•Sialolithiasis is thought to affect approximately 1% of the population based on autopsy studies.

•It has been estimated to represent more than 50% of major salivary gland disease and is the most common cause of acute and chronic salivary gland infections.

•Approximately 85% of sialolithiasis occurs in the submandibular gland, 10% in the parotid gland, 5% in the sublingual gland, and the incidence of this pathology is rare in the sublingual gland and minor salivary glands.

•80% of submandibular sialoliths are radioopaque, while 40% of sialoliths of the parotid gland are radio-opaque.

•Systemic disorders of calcium metabolism do not seem to represent predisposing factors to sialolithiasis. The one exception to this rule is gout, where a higher incidence of uric acid stones has been observed.

•75–85% of submandibular stones are located in the duct, while parotid stones are located

in the hilum or gland parenchyma in at least half of cases.

•Several “great imitators” of submandibular sialolithiasis exist, including scrofula, phleboliths, osteomas, and occasionally carotid plaques.

•Numerous techniques are available to treat sialolithiasis including surgical sialolithotomy with or without sialodochoplasty, sialoendoscopy with sialolithotomy, intracorporeal or extracorporeal lithotripsy, or gland removal.

References

Anneroth G, Hansen LS. 1983. Minor salivary gland calculi. A clinical and histopathological study of 49 cases. Int J Oral Maxillofac Surg 12:80–89.

Arzoz E, Santiago A, Esnal F, Palomero R. 1996. Endoscopic intracorporeal lithotripsy for sialolithiasis. J Oral Maxillofac Surg 54:847–850.

Baurmash HD. 2004. Submandibular salivary stones: Current management modalities. J Oral Maxillofac Surg 62:369–378.

Baurmash H, Dechiara SC. 1991. Extraoral parotid sialolithotomy. J Oral Maxillofac Surg 49:127–132.

Berry RL. 1995. Sialadenitis and sialolithiasis: Diagnosis and management. Oral Maxillofac Surg Clin North Am

7:479–503.

Bodner L. 1993. Salivary gland calculi: Diagnostic imaging and surgical management. Compend Contin Educ Dent 14:572–584.

Drage NA, Wilson RF, McGurk M. 2002. The genu of the submandibular duct—is the angle significant in salivary gland disease? Dentomaxillofacial Radiology

31:15–18.

Escudier MP. 1998. The current status and possible future for lithotripsy of salivary calculi. Atlas Oral Maxillofac Surg Clin North Am 6:117–132.

Friedlander AH, Freymiller EG. 2003. Detection of radia- tion-accelerated atherosclerosis of the carotid artery by panoramic radiography. JADA 134:1361–1365.

Karas ND. 1998. Surgery of the salivary ducts. Atlas of the Oral Maxillofac Surg Clin North Am 6:99–116.

Kasaboglu O, Er N, Tumer C, Akkocaoglu M. 2004. Micromorphology of sialoliths in submandibular salivary gland: A scanning electron microscope and x-ray diffraction analysis. J Oral Maxillofac Surg 62:1253–1258.

King CA, Ridgley GV, Kabasela K. 1990. Sialolithiasis of the submandibular gland: A case report. Compend Contin Educ Dent 11:262–264.

Lagha NB, Alantar A, Samson J et al. 2005. Lithiasis of minor salivary glands: Current data. Oral Surg Oral Med Oral Pathol 100:345–348.

Lustmann J, Regev E, Melamed Y. 1990. Sialolithiasis: A survey on 245 patients and a review of the literature. Int J Oral Maxillofac Surg 19:135–138.

Lutcavage GJ, Schaberg SJ. 1991. Bilateral submandibular sialolithiasis and concurrent sialadenitis: A case report.

J Oral Maxillofac Surg 49:1220–1222.

Mandel L. 2006. Tuberculous cervical node calcifications mimicking sialolithiasis: A case report. J Oral Maxillofac Surg 64:1439–1442.

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Mandel L, Surattanont F. 2004. Clinical and imaging diagnoses of intramuscular hemangiomas: The wattle sign and case reports. J Oral Maxillofac Surg 62:754–758.

McGurk M, Escudier MP, Brown JE. 2004. Modern management of salivary calculi. Br J Surg 92:107–112.

McGurk M, Makdissi J, Brown JE. 2004. Intra-oral removal of stones from the hilum of the submandibular gland: Report of technique and morbidity. Int J Oral Maxillofac Surg 33:683–686.

Miloro M. 1998. The surgical management of submandibular gland disease. Atlas Oral Maxillofac Surg Clin North Am 6:29–50.

Miloro M, Goldberg MH. 2002. Salivary gland infections. In: Topazian RG, Goldberg MH, Hupp JR (eds.), Oral and Maxillofacial Infections (4th ed.). Philadelphia: W.B. Saunders, pp. 279–293.

Nakayama E, Yuasa K, Beppu M et al. 2003. Interventional sialendoscopy: A new procedure for noninvasive insertion and a minimally invasive sialolithectomy. J Oral Maxillofac Surg 61:1233–1236.

Ottaviani F, Capaccio P, Campi M et al. 1996. Extracorporeal electromagnetic shock-wave lithotripsy for salivary gland stones. Laryngoscope 106:761–764.

Park JS, Sohn JH, Kim JK. 2006. Factors influencing intraoral removal of submandibular calculi. Otolaryngol Head Neck Surg 135:704–709.

Rontal M, Rontal E. 1987. The use of sialodochoplasty in the treatment of benign inflammatory obstructive submandibular gland disease. Laryngoscope 97:1417– 1421.

Seward GR. 1968. Anatomic surgery for salivary calculi. I: Symptoms, signs, and differential diagnosis. Oral Surg Oral Med Oral Pathol 25:150–157.

Williams MF. 1999. Sialolithiasis. Otolaryngol Clin North Am 32:819–834.

Chapter 6

Systemic Diseases Affecting the

Salivary Glands

Outline

Introduction Sjogren’s Syndrome

Clinical Manifestations of Sjogren’s Syndrome Mikulicz’s Disease and the Benign Lymphoepithelial

Lesion

Diagnosis of Sjogren’s Syndrome with Salivary Gland Biopsy

Histopathology of Sjogren’s Syndrome Sarcoidosis

Clinical Manifestations of Sarcoidosis

Diagnosis of Sarcoidosis with Salivary Gland Biopsy Histopathology of Sarcoidosis

Sialosis

Clinical Manifestations of Sialosis

Diagnosis of Sialosis with Salivary Gland Biopsy Histopathology of Sialosis

Summary

References

Introduction

A number of systemic diseases result in infiltration of the salivary glands. These include immunemodulated or idiopathic diseases such as sarcoidosis, Sjogren’s disease, sialosis, and lymphoepithelial lesions, as well as lymphoma, a malignant proliferation of B or T lymphocytes. Each of these processes involves multiple physiologic systems and may be diagnosed at an early stage with salivary gland biopsy. It is the purpose of this chapter to describe the clinical features of salivary gland involvement of systemic diseases.

Sjogren’s Syndrome

Sjogren’s syndrome is an inflammatory autoimmune disease that manifests as a chronic, slowly

progressive disease characterized by keratoconjunctivitis sicca and xerostomia. Since 1965, it has been defined as a triad of dry eyes, dry mouth, and rheumatoid arthritis or other connective tissue diseases (Daniels 1991). This process may evolve from an exocrine organ–specific disorder to an extraglandular multisystem disease affecting the lungs, kidneys, blood vessels, and muscles (Table 6.1). These features are believed to be the result of immune system activation with the production of various autoantibodies with lymphocyte invasion of the salivary and lacrimal glands and other affected organs. The autoantibodies include those produced to the ribonucleoprotein particles SS-A/ Ro and SS-B/La, and these are thought to interfere with muscarinic receptors (Garcia-Carrasco, Fuentes-Alexandro, and Escarcega et al. 2006). One study identified IgG from patients with primary Sjogren’s syndrome containing autoantibodies capable of damaging saliva production and contributing to xerostomia (Dawson, Stanbury, and Venn et al. 2006). Other mechanisms of glandular dysfunction include destruction of glandular elements by cell-mediated mechanisms; secretion of cytokines that activate pathways bearing the signature of type 1 and 2 interferons; and secretion of metalloproteinases (MMP) that interfere with the interaction of the glandular cell with its extracellular matrix (Garcia-Carrasco, FuentesAlexandro, and Escarcega et al. 2006). In addition, increased MMP-3 and MMP-9 expression has been found to be responsible for acinar destruction in Sjogren’s syndrome (Perez, Kwon, and Alliende et al. 2005). These substantial increases in MMP expression in diseased labial salivary glands may be potentiated by moderate decreases in tissue inhibitors of matrix metalloproteinases (TIMP).

Primary Sjogren’s syndrome is designated when it is not associated with other connective tissue diseases. This notwithstanding, evidence exists that shows genetic aggregation of autoim-

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Table 6.1. Frequency of extraglandular findings in primary Sjogren’s syndrome.

Clinical Involvement	Percent
Arthritis	60
Kidney	9
Liver	6
Lung	14
Lymphadenopathy	14
Lymphoma	6
Myositis	1
Peripheral neuropathy	5
Raynaud’s phenomenon	35
Splenomegaly	3

mune diseases in families of patients with primary Sjogren’s syndrome (Anaya et al. 2006). The suggestion is that autoimmune diseases in general may aggregate as a trait favoring a common immunogenetic origin for diverse autoimmune phenotypes, such that a risk factor exists for the development of primary Sjogren’s syndrome and other autoimmune diseases. Secondary Sjogren’s syndrome is defined when the disease is associated with other clinically expressed autoimmune processes, specifically rheumatoid arthritis, systemic lupus erythematosus, myositis, biliary cirrhosis, systemic sclerosis, chronic hepatitis, cryoglobulinemia, thyroiditis, and vasculitis. Following rheumatoid arthritis, Sjogren’s syndrome is the second most common autoimmune rheumatic disorder (Moutsopoulos 1993). Eight to 10 years are generally required for the disorder to progress from initial symptoms to the development of the syndrome. Although typically seen in middle-aged women, Sjogren’s syndrome can occur in all ages and in males. It has been estimated that 80–90% of patients are women, and that the mean age at diagnosis is 50 years (Daniels 1991).

CLINICAL MANIFESTATIONS OF SJOGREN’S SYNDROME

Most patients with Sjogren’s syndrome develop symptoms related to decreased salivary gland and lacrimal gland function. Primary Sjogren’s syndrome patients generally complain of dry eyes, often described as a sandy or gritty feeling under the eyelids. Other symptoms such as itching of the

eyes, eye fatigue, and increased sensitivity to light can accompany the primary symptoms. Many of these symptoms are due to the destruction of corneal and bulbar conjunctival epithelium and come under the diagnosis of keratoconjunctivitis sicca. This disorder is assessed by tear flow and composition. Tear flow is measured using the Schirmer test, while tear composition can be determined by tear break-up time or tear lysozyme content. The Schirmer test is considered positive when filter paper wetting of less than 5 mm occurs in 5 minutes, and suggests clinically significant keratoconjunctivitis sicca (Moutsopoulos 1993). There are, nonetheless, numerous false positive and negative results, such that the predictive value is limited. The integrity of the corneal and bulbar conjunctiva may be assessed using the Rose Bengal staining procedure and slip lamp examination. Punctate corneal ulcerations and attached filaments of corneal epithelium indicative of corneal and bulbar conjunctival epithelial destruction are noted on slip lamp examination in Sjogren’s patients.

Xerostomia is the second principal symptom of Sjogren’s syndrome. Xerostomia can be documented by salivary flow measurements, parotid sialography, and salivary scintigraphy. Salivary flow measurements must be adjusted for age, time of day, gender, and concomitant medications. Patients with dry mouths complain of a burning oral discomfort and difficulty in chewing and swallowing dry foods. Xerostomia is commonly associated with changes in taste and the inability to speak continuously for longer than several minutes.

Salivary gland enlargement occurs in as many as 30% of patients with Sjogren’s syndrome during the course of their illness, with the parotid gland being most often enlarged (Figure 6.1) (Kulkarni 2005). Bilateral painful submandibular glands have been described as a presenting symptom of this syndrome (Kulkarni 2005). While the parotid glands are most commonly enlarged, they may be the last glands to be affected in patients with Sjogren’s syndrome from the standpoint of decreased saliva production (Pijpe, Kalk, and Bootsma et al. 2007). The parotid glands have a longer-lasting secretory capacity in patients with Sjogren’s syndrome, and therefore are the last glands to manifest hyposalivation during the disease. In the more advanced stages of the disease, both unstimulated and stimulated submandibular, sublingual, and parotid func-

Figure 6.1. A 36-year-old woman with a known history of Sjogren’s syndrome associated with rheumatoid arthritis. She described a recent history of painful swelling of the right parotid gland such that an incisional parotid biopsy was recommended.

Lymphoma

Lymphoma in Sjogren’s syndrome

Sjogren’s syndrome

Lymphoma in benign	Benign lymphoepithelial lesion
lymphoepithelial lesion	in Sjogren’s syndrome

Benign lymphoepithelial lesion

Figure 6.2. The association between the lymphoepithelial lesion, Sjogren’s syndrome, and lymphoma.

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tions fall to a low level. The accelerated development of dental caries is also noted. Enlargement of the lacrimal glands is uncommon. Even when the salivary glands are not enlarged, they always exhibit lymphohistiocyte-mediated acinar destruction (Marx 1995). When enlarged, however, they show features of the benign lymphoepithelial lesion (BLL) in almost all cases. These lesions may occur in patients who do not have Sjogren’s syndrome. Furthermore, they may undergo malignant transformation to lymphomas in patients with or without Sjogren’s syndrome (Figure 6.2). This concept, as well as the entity Mikulicz’s disease, is clearly worthy of additional discussion.

MIKULICZ’S DISEASE AND THE BENIGN LYMPHOEPITHELIAL LESION

The pathologic entity known as the benign lymphoepithelial lesion was once referred to as Mikulicz’s disease. The German surgeon Johann Mikulicz first described the benign lymphoepithelial lesion in 1888 in a report of a single case of lacrimal gland involvement (Daniels 1991). The lacrimal gland enlargement was followed by enlargement of the submandibular and parotid glands, as well as minor salivary gland tissue. The term “Mikulicz’s disease” was subsequently applied to a variety of cases of bilateral salivary or lacrimal gland enlargement, including those caused by sarcoidosis, lymphoma, tuberculosis, or syphilis. The term “lymphoepithelial lesion” was proposed by Godwin in 1952 to describe parotid gland lesions previously called Mikulicz’s disease, adenolymphoma, chronic inflammation, lymphoepithelioma, or lymphocytic tumor (Godwin 1952). One year later, Morgan and Castleman observed numerous similarities of the benign lymphoepithelial lesion to the histopathology of Sjogren’s syndrome and proposed that Mikulicz’s disease is not

a distinct clinical and pathologic entity but rather one manifestation of the symptom complex of the syndrome (Morgan and Castleman 1953). The benign lymphoepithelial lesion may become large enough to present as a mass resembling a parotid tumor (Figure 6.3).

Acinar degeneration and hyperplasia and metaplasia of the ducts led to the formation of the pathognomonic epimyoepithelial islands, which define the condition. Whether myoepithelial cells or ductal basal cells are responsible for these islands has been questioned. An immunohistochemical investigation has shown that myoepithelial cells do not play a role in the formation of these islands and they should be designated lymphoepithelial metaplasia (Ihrler, Zietz, and Sendelhofert et al. 1999). The condition is often a manifestation of Sjogren’s syndrome or other immunological abnormality but may occur outside the Sjogren’s disease process. Usually the lesion starts unilaterally but becomes bilateral in the parotids (Figure 6.4). It is less common in the submandibular and minor salivary glands (Figure 6.5).

The lesion may reach a large size, although it is usually asymptomatic. It may be diagnosed by fine needle aspiration if the etiology is uncertain and may require removal by parotidectomy for aesthetic reasons. Sudden growth or pain may be an ominous feature, as a benign lymphoepithelial lesion can undergo malignant change and is perhaps not as benign as its name suggests. The lymphocytic component can undergo change to MALT lymphoma (see chapter 11), particularly in Sjogren’s syndrome (Abbondanzo 2001) but also in HIV infections (Del Bono, Pretolesi, and Pontali et al. 2000). Recurrent benign lymphoepithelial lesion may also undergo malignant change of its epithelial component to become an undifferentiated carcinoma with lymphoid stroma (see chapter 8) (Cai, Wang, and Lu 2002).

a			b
	Figures 6.3a and 6.3b. A 75-year-old woman with a left parotid mass. Fine needle aspiration biopsy suggested lymphoma,
	leading to superficial parotidectomy. Histopathology identified benign lymphoepithelial lesion.

a b

Figures 6.4a and 6.4b. A 45-year-old woman diagnosed with Sjogren’s syndrome with bilateral parotid lesions shown on axial (a) and coronal images (b).

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