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Necrotizing sialometaplasia: a practical approach to the diagnosis.

Necrotizing sialometaplasia (NSM) is a benign, self-healing lesion of salivary glands, which represents less than 1% of biopsied oral lesions. (1) It may arise in any area containing salivary gland tissue. Classically, it involves the mucoserous glands of the hard palate. Other sites where it has been reported include nasal cavity, trachea, parotid gland, sublingual gland, submandibular gland, larynx, buccal mucosa, maxillary sinus, tongue, tonsil, and retromolar trigone. (2-5) Up to 10% of cases have been reported in major salivary glands.6 Collective examination of 184 cases reported in the literature reveals that the condition occurs in men in 65% of cases. (3) Herein is a discussion of the clinical and pathologic findings, potential pathogenesis, and differential diagnosis of this entity.


The lesion is usually painful and presents as a sharply circumscribed ulcer, frequently 1 to 3 cm in diameter. Palate involvement usually appears as a single, unilateral ulcer on the posterior hard palate or at the junction of the hard and soft palates. The ulcer borders are often erythematous and may be raised. In some instances, the mucosal surface is intact and the lesion is raised and fluctuant, giving the false impression of an abscess.

There is a wide range in the age at presentation (1.5-83 years), although most patients are older than 40 years. (3,7) The incidence appears to be 2 to 3 times greater in males than females. (8) Patients commonly consult their dentist with fear for carcinoma and with a history of a noticeable lesion of a few weeks' duration.


The most commonly proposed and generally accepted etiology for NSM relates to ischemia. In 25 of 69 cases reported by the Armed Forces Institute of Pathology, the process was seen subsequent to a surgical procedure. (3) Other traumatic injuries, such as dental injection, blunt force trauma, denture wear, alcohol and tobacco use, as well as upper respiratory infections, have been implicated as potential predisposing factors. Romagosa and colleagues (9) reported 3 cases occurring in the trachea after intubation. Similarly, it has been described in the larynx secondary to atheromatous embolization. (10)

Anneroth and Hansen4 proposed 5 histologic stages in the development and evolution of necrotizing sialometaplasia: infarction, sequestration, ulceration, repair, and healing. They emphasized that these stages could overlap and would be dependent upon the extent and severity of damage.

An emerging associated etiology is that seen in the setting of bulimia, a history often difficult to elicit. Bulimia is a well-recognized eating disorder in which individuals binge eat unusually large quantities of food and induce vomiting by a mechanical gag reflex or by ingesting syrup of ipecac. According to the American Psychiatric Association, anorexia nervosa and bulimia nervosa affect as many as 3% of adolescent and young adult females, and the incidence of anorexia nervosa appears to have increased in recent decades. (11) In a culture where "thin is in," it would seem reasonable to conjecture that bulimia is most likely underreported and, hence, so is its correlation with NSM.

Necrotizing sialometaplasia in the context of bulimia was first reported in 1998 in 2 patients and has since been reported in 5 and possibly 6 cases. (7,12-14) All patients were white women between the ages of 29 and 32 and the site of involvement for all was the palate (Table 1). Other oral complications frequently reported in association with bulimia include sialadenosis, which is hypertrophy of serous acinar cells, often with infiltration of adiopocytes and without an inflammatory component. (15) This is most commonly manifested in the parotid gland and is frequently bilateral. Xerostomia, dental caries, tooth erosion, and demineralization of enamel and dentin are additional consequences of repetitive, chronic vomiting.

A similar phenomenon to NSM has been described in the breast, lung, and skin. (16-19) In the skin, it has been referred to as eccrine squamous syringometaplasia, where it has been reported in association with chronic ulcers, cytomegalovirus, herpesvirus, underlying neoplasia, and chemotherapeutic agents. (16,20,21)


There are 5 key histopathologic features of NSM, as listed in Table 2. Pseudoepitheliomatous hyperplasia of the overlying squamous mucosa is commonly present when the lesion involves the palate. Considering the extent to which atypia can occur in pseudoepitheliomatous hyperplasia overlying a granular cell tumor, one can similarly extrapolate what can be found in association with NSM. The squamous metaplasia of minor salivary gland ducts and acini may contain apoptotic cells and areas of inflammation as well as mucin spillage. The preservation of the normal lobular architecture of the salivary glands is a key feature.

For illustrative purposes, a discussion of the characteristics of NSM follows that uses a previously published case,7 with additional immunohistochemistry results not previously reported.

Case History

A 32-year-old woman with a history of bulimia presented with a painful lesion on the left side of the hard palate of 12 weeks' duration. On biopsy, this lesion was initially diagnosed as a mucoepidermoid carcinoma (Figure 1, a and b). The biopsy specimen was subsequently sent to a large tertiary cancer center where the diagnosis rendered was of a superficially invasive well-differentiated squamous cell carcinoma. The patient went to a third treatment center, where she underwent a conservative complete resection of the area. No lymph nodes were dissected. The slides from the initial biopsy and subsequent excision were then reviewed by another expert, who rendered a diagnosis of necrotizing sialometaplasia. A 6month follow-up of the patient demonstrated complete resolution of any palatal lesion; however, the patient's eating disorder remained uncontrolled.

Histologic features that help exclude the diagnosis of NSM include perineural invasion, the presence of apparently neoplastic goblet cells or proliferation thereof, and atypical mitoses. The extent of cellular necrosis must be evaluated in context. A few necrotic single cells are far less worrisome than islands of necrotic squamous cells. Similarly, while NSM may demonstrate cytologic atypia, marked nuclear pleomorphism in conjunction with high nuclear to cytoplasmic ratios should elicit concern for a malignant neoplasm (Figure 2, a and b).


The 2 most important differential diagnoses include squamous cell carcinoma and mucoepidermoid carcinoma. An entity described in the dental literature as nicotinic stomatitis, associated with cigar and pipe smoking, has a quite similar histologic and clinical presentation. It tends to be multifocal and grossly more punctate, with multiple foci localized to the palate. (22) These latter lesions are not considered preneoplastic and resolve upon cessation of smoking.




Clinical history is helpful in recognizing NSM, although not all cases will be correlated with an obvious etiologic event. But when possible, it is of tremendous utility to interpret these lesions in the correct clinical context. Cytologic atypia can be severe with single-cell necrosis and hyperchromatic, angulated cells. In a major salivary gland, such as the parotid, an associated or nearby proliferation of tissue culturelike fibroblasts and granulation tissue may be present (Figure 3, a and b). It is the maintenance of lobular architecture, best seen at low power, which is the best histologic clue (Figure 4).

Reactive squamous epithelium can appear alarmingly atypical, with single-cell necrosis; hence, the application of immunohistochemistry has been attempted and proposed as an adjunct to diagnosis. (23,24) The incorporation of an antibody panel including myoepithelial markers (smooth muscle antibody, p63, calponin), basement membrane markers (laminin, collagen type IV), E-cadherin, and various cytokeratins (CK5, CK6, CK7, CAM 5.2) has been suggested (23,24) (Figure 5, a through d; Figure 6, a through d). These assays may be helpful when the basal layer surrounding the metaplastic squamous epithelium stains for myoepithelial markers and the metaplastic mucosa, which is without goblet cells, does not. This may better elucidate the preserved lobular architecture still apparent on hematoxylin-eosin. Both MIB-1 (Ki-67) and p53 can stain positively in either benign or reactive squamous epithelium; labeling is generally more intense and is increased in malignancy, but, alone, neither is diagnostic (Figure 7, a and b; Figure 8, a through c). If a diagnosis of NSM is unclear on hematoxylin-eosin staining, the aforementioned antibodies may be supportive of a diagnosis but will not be pathognomonic. All test results must be interpreted in relation to each another, as well as within the clinical setting. Therefore, at present, multiple serial sections and a properly oriented tissue section remain the mainstay of diagnosis of NSM.




The proposed etiology of NSM is vascular ischemia. Both physical and chemical trauma have been reported antecedent to the development of these lesions. Surgery, radiation, inflammation, and bulimia have all been associated with NSM. The treatment is symptomatic and lesions will undergo spontaneous healing within 2 to 3 months. Necrotizing sialometaplasia does not usually recur, and if it is properly diagnosed preoperatively, surgical excision is not necessary. Lesions that fail to resolve should be reassessed.

Interestingly, the Third National Health and Nutrition Examination Survey, conducted in the United States for a period of 6 years, revealed that of 17 235 adult patients, 25.9% had clinically detectable palate lesions on oral mucosal examination. (25) These lesions ranged from infectious and benign to preneoplastic. Smokers had a higher prevalence of palatal lesions than did nonsmokers. Perhaps the palate is more sensitive to ischemia, in a variety of forms, more so than are other areas of the oral mucosa.


The foremost characteristic histopathologic features of NSM are the overall preservation of lobular architecture and ductal squamous metaplasia. The differential diagnoses of greatest import include mucoepidermoid carcinoma and squamous cell carcinoma. The clinical scenario of a nonhealing palatal ulcer in an adolescent or young adult patient with clinical signs of bulimia should greatly increase suspicion for NSM, particularly because squamous cell carcinoma of the palate is uncommon in young females. While there is no definitive immunophenotype--and a properly oriented hematoxylin-eosin section remains the gold standard for diagnosis--use of MIB-1 (Ki67), p53, calponin, and CK7 may be helpful, so long as they are interpreted in relation to each other. Avoidance of overtreatment of a nonneoplastic condition is the ultimate goal in maintaining the dictum primum non nocere.

Accepted for publication January 19, 2009.


(1.) Mesa ML, Gertler RS, Schneider LC. Necrotizing sialometaplasia: frequency of histologic misdiagnosis. Oral Surg Oral Med Oral Pathol. 1984;57(1):71-73.'

(2.) Schoning H, Emshoff R, Kreczy A. Necrotizing sialometaplasia in two patients with bulimia and chronic vomiting. Int J Oral Maxillofac Surg. 1998;27(6): 463-465.

(3.) Brannon RB, Fowler CB, Hartman KS. Necrotizing sialometaplasia: a clinicopathological study of sixty-nine cases and review of the literature. Oral Surg. 1991;72:317-325.

(4.) Anneroth G, Hansen LS. Necrotizing sialometaplasia: the relationship of its pathogenesis to its clinical characteristics. Int J Oral Surg. 1 982;1 1:283-291.

(5.) Romagosa V, Bella MR, Truchero C, Moya J. Necrotizing sialometaplasia (adenometaplasia) of the trachea. Histophatology. 1992;21(3):280-282.

(6.) Farina D, Gavazzi E, Avigo C, Borghesi A, Maroldi R. MRI findings of necrotizing sialometaplasia. Br J Radiol. 2008;81(966):e173-e175. doi: 10.12 59/bjr/ 51447334.

(7.) Solomon LW, Merzianu M, Sullivan M, Rigual NR. Necrotizing sialometaplasia associated with bulimia: case report and literature review. Oral SurgOral Med Oral Pathol Oral Radiol Endod. 2007;103(2):e39-e42. &_user=281587&rdoc=1&.fmt=&.orig=search&.sort=d&view=c&. acct=C000016018_version=1&_urlVersion=.

(8.) Penner CR, Thompson LD. Necrotizing sialometaplasia. Ear Nose Throat J. 2003;82(7):493-494.

(9.) Ramagosa V, Bella MR, Truchero C, Moya J. Histopathology. 1992;21(3): 280-282.

(10.) Walker Gk, Fecher RE, Johns ME, Teja K. Necrotizing sialometaplasia of the larynxsecondary to atheromatous embolization. Am J Clin Pathol. 1982;77(2): 221-223.

(11.) American Psychiatric Association Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. 4th ed. Washington, DC: American Psychiatric Association; 1994.

(12.) Schoning H, Emshoff R, Kreczy A. Necrotizing sialometaplasia in two patients with bulimia and chronic vomiting. Int J Oral Maxillofac Surg. 1998;27: 463-465.

(13.) Scully C, Everson J. Sialosis and necrotizing sialometaplasia in bulimia: a case report. Int J Oral Maxillofac Surg. 2004;33:808-810.

(14.) Lombardi T, Samson J, Kuffer R. Subacute necrotizing sialadenitis: a form of necrotizing sialometaplasia? Arch Otolaryngol Head Neck Surg. 2003;129: 972-975.

(15.) Aframian DJ. Anorexia/bulimia-related sialadenosis of palatal and minor salivary glands [letter]. J Oral Pathol Med. 2005;34:383.

(16.) Hurt MA, Halvorson RD, Petr FC Jr, Cooper JT Jr, Friedman DJ. Eccrine squamous syringometaplasia: a cutaneous sweat gland reaction in the histologic spectrum of 'chemotherapy-associated eccrine hydradenitis' and 'neutrophiliceccrine hydradenitis.' Arch Dermatol. 1990;126(1):73-77.

(17.) Hurt MA, Diaz-Arias AA, Rosenholtz MJ, Havey AD, Stephenson HE Jr. Mod Pathol. 1998;1(5):385-390.

(18.) Zschoch H. Mucus gland infarct with squamous epithelial metaplasia in the lung: a rare site of so-called necrotizing sialometaplasia [in German]. Path ologe. 1992;13(1):45-48.

(19.) King Dt, Barr RJ. Syringometaplasia: mucinous and squamous variants. J Cutan Pathol. 1979;6(4):284-291.

(20.) Dauden E, Porras JI, Buezo GF, Garcfa-Dfez A. Eccrine squamous syringometaplasia and cytomegalovirus. Am JDermatopathol. 2000;22(6):559-561.

(21.) Serrano T, Saez A, Moreno A. Eccrine squamous syringometaplasia: a prospective clinicopathologic study. J Cutan Pathol. 1993;20(1):61-65.

(22.) Imbery TA, Edwards PA. Necrotizing sialometaplasia: literature review and case reports. J Am Dent Assoc. 1996;127:1087-1092.

(23.) Zarovnaya E, Black C. Distinguishing pseudoepitheliomatous hyperplasia from squamous cell carcinoma in mucosal biopsy specimens from the head and neck. Arch Pathol Lab Med. 2005;129:1032-1036.

(24.) Rizkalla H, Toner M. Necrotizing sialometaplasia versus invasive carcinoma of the head and neck: the use of myoepithelial markers and keratin subtypes as an adjunct to diagnosis. Histopathology. 2007;51:184-189.

(25.) Shulman JD, Beach MM, Rivera-Hidalgo F. The prevalence of oral mucosal lesions in U.S. adults: data from the Third National Health and Nutrition Examination Survey, 1988-1994. JAm Dent Assoc. 2004;135(9):1279-1286.

Diane L. Carlson, MD

From the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.

The author has no relevant financial interest in the products or companies described in this article.

Presented in part at The Surgical Pathology of Neoplastic Diseases course, Memorial Sloan-Kettering Cancer Center, New York, New York, May 12-16, 2008.

Reprints: Diane L. Carlson, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (e-mail:
Table 1. Reported Cases of Necrotizing Sialometaplasia
Associated With Bulimia

                      No. of                    Clinical
Source, y             Cases    y/Sex   Race     Presentation

Schoning et al,         2      20/F    White    Ulcer with
(12) 1998                                       numbness
                               21/F    White    Ulcer with
                                                no pain or
Scully and Everson,     1      29/F    White    Bilateral ul-
(13) 2004                                       cers
Lombardi et al,         1      23/F    NA       Mild pain
(14,a) 2003
Solomon et al, (7)      1      32/F    White    Painful ulcer
2007                                            for 12 wk

                                       Size of       Time to
Source, y             Site             Lesion(s)     Resolution

Schoning et al,       Posterior hard   2 X 2 cm      4 wk, untreated
(12) 1998             palate
                      Hard palate      1 X 2 cm      2 mo, untreated
Scully and Everson,   Posterior pal-   [approximately4 wk, untreated
(13) 2004             ate
Lombardi et al,       Hard palate      1 cm          3 wk, untreated
(14,a) 2003
Solomon et al, (7)    Hard palate      1.5 X 2.0     6 mo, post
2007                                   cm            surgical

Source, y             Clinical History

Schoning et al,       3-y history of bulimia with
(12) 1998             50 episodes of weekly
                      3-y history of bulimia with
                      20 episodes of weekly
Scully and Everson,   2-y history of bulimia
(13) 2004
Lombardi et al,       Anorexia/bulimia
(14,a) 2003
Solomon et al, (7)    Bulimia of uncertain dura-
2007                  tion

Abbreviation: NA, not available.

(a) Reported as subacute necrotizing sialadenitis and appears
to have features of necrotizing sialometaplasia.

Table 2. Histologic Features of Necrotizing

* Pseudoepitheliomatous hyperplasia

* Squamous metaplasia of ducts and acini

* Preservation of lobular architecture

* Lobular infarction with or without mucin spillage

* Inflammation secondary to extravasation of mucin
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Author:Carlson, Diane L.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Case study
Date:May 1, 2009
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