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. 2021 Apr 26;15(4):1172–1184. doi: 10.1007/s12105-021-01330-8

Histopathologic Spectrum of Intraoral Irritant and Contact Hypersensitivity Reactions: A Series of 12 cases

Diana Wang 1,2,✉, Sook-Bin Woo 1,2,3
PMCID: PMC8633165  PMID: 33904012

Abstract

Background

Irritant contact stomatitis (ICS) and contact hypersensitivity stomatitis (CHS) are often caused by alcohol, flavoring agents and additives in dentifrices and foods, and contactants with high or low pH. A well-recognized contactant for ICS is Listerine™ mouthwash, while that for CHS is cinnamic aldehyde. However, many other flavoring agents and even smokeless tobacco are contactants that cause mucosal lesions that are entirely reversible. The objective of this study is to 1) present cases of ICS and CHS with a clear history of a contactant at the site and the histopathologic features of the resulting lesion and 2) define the histopathologic features that characterize such lesions.

Methods

12 cases of ICS and CHS with known contactants that exhibited distinct histopathologic patterns were identified.

Results

ICS are characterized by three patterns in increasing order of severity namely: 1) superficial desquamation, 2) superficial keratinocyte edema, and 3) keratinocyte coagulative necrosis with/out spongiosis and microabscesses. CHS is characterized by two patterns namely plasma cell stomatitis with an intense plasma cell infiltrate and a lymphohistiocytic infiltrate with or without non-necrotizing granulomatous inflammation. Three patterns of the latter are recognized: (1) lymphohistiocytic infiltrate at the interface with well-formed or loosely aggregated non-necrotizing granulomas; (2) lymphohistiocytic infiltrate at the interface with peri- and para-vascular lymphohistiocytic nodules; and (3) lymphohistiocytic infiltrate at the interface with peri- and para-vascular lymphohistiocytic nodules containing non-necrotizing granulomas. The same contactant may elicit ICS and CHS, while one histopathologic pattern may be brought on by various contactants.

Conclusion

ICS and CHS have distinct histologic patterns. Recognizing that these patterns are caused by contactants would help clinicians manage such mucosal lesions.

Keywords: Contact stomatitis, Contact hypersensitivity stomatitis, Irritant contact stomatitis, Cinnamic aldehyde, Smokeless tobacco lesion, Non-necrotizing granuloma

Introduction

Contact stomatitis is defined as an inflammatory process that involves the oral mucosa in contact with an irritant or allergen. There are two main types of contact stomatitis: irritant contact stomatitis (ICS) and contact hypersensitivity stomatitis (CHS) [1, 2]. Similar to irritant contact dermatitis, ICS involves a local reaction after a single or repeated, direct surface mucosal exposure to a physical or chemical irritant such as to aspirin or smokeless tobacco. [3, 4] The severity of mucosal damage is based on the caustic nature of, and frequency and duration of exposure to the irritant [5]. CHS is analogous to contact hypersensitivity dermatitis and is a T cell-mediated, delayed type IV hypersensitivity reaction in response to a second or successive exposure of contact allergens. These small organic molecules generate an immunogenic response leading to the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and various cytokines [1, 2, 6].

ICS-associated lesions typically presents with mucosal sloughing, erythema, ulceration and/or white plaques and a well-known example of a severe lesion is an aspirin burn [4, 7]. CHS in reaction to cinnamic aldehyde is well-recognized and this may present as edema and vesicles, and erythema with or without white papules and plaques [8–11]. Although the underlying etiopathogenesis for ICS and CHS are different, the clinical appearance and histologic findings are often very similar and it may be difficult for clinicians to differentiate between the two. A thorough history, clinical examination, biopsy, avoidance of the suspected agent, and sometimes patch testing are essential in arriving at a correct diagnosis [6, 12].

The purpose of this study is to report five distinct histopathological features of intraoral irritant and contact hypersensitivity reaction cases with known contactants.

Method

Cases of ICS and CHS with known contactants were identified from January 2013 to June 2019 from the archives of Strata Dx, a surgical pathology laboratory affiliated with the Harvard School of Dental Medicine in Boston, MA, USA as well as from the Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital. Hematoxylin and eosin-stained slides and the results of histochemical and immunoperoxidase studies were reviewed. Clinical information and photographs were provided by patients’ referring providers.

Results

Irritation Contact Stomatitis

There were 6 cases of ICS that exhibited 3 distinct histological patterns as follows: (1) detached strips of degenerated and desquamated keratinocytes, (2) demarcated superficial keratinocyte edema, and (3) epithelial coagulative necrosis with spongiotic pustules and intraepithelial microabscesses (Table 1).

Table 1.

Clinicopathologic features of Cases 1–12

Histological pattern Case No Age Gender Contac Location Clinical appearance
(1) Detached strips of degenerated, desquamated keratinocytes 1 58 M Listerine™ mouth rinse Anterior floor of mouth superficial sloughing
2 72 M Listerine™ mouth rinse Lower lip mucosa, bilateral buccal mucosa and ventral floor of mouth Grey-white lesions and white plaque
(2) Superficial keratinocyte edema sharply demarcated from underlying keratinocytes 3 37 M tobacco Left maxillary vestibule white plaque
4 58 F Varying flavors of chewing gum Right lateral tongue white plaque
5 46 F Nicorette™ lozenges Left lateroventral tongue white plaque
(3) Epithelial coagulative necrosis, spongiotic pustules and intraepithelial microabscesses 6 73 F Tums™ Right ventral tongue white plaque
(4) Sheets of polyclonal plasma cell infiltrate 7 66 M Sensodyne Extra-Whitening™ toothpaste Maxillary and mandibular facial gingiva, right and left buccal mucosa, left mandibular buccal vestibule diffuse erythema and ulceration
(5) Interface lymphohistiocytic infiltrate ± granulomatous inflammation in a peri- and para-vascular location ± non-necrotizing granulomas 8 68 F Listerine Fresh Breath Strips™ Hard palatal mucosa white plaque
9 20 F Crest Pro-health™toothpaste Maxillary and mandibular facial gingiva diffuse erythema
10 62 F Trident™ cinnamon-flavored chewing gum Right buccal mucosa white plaque
11 64 F Mint-flavored chewing gum Left maxillary vestibule N/A
12 46 F Nicorette™ gum right buccal mucosa white plaque
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Case 1

A 58-year-old male presented with superficial sloughing of the anterior floor of mouth in contact with Listerine™ mouthwash. The biopsy revealed thinly parakeratinized stratified squamous epithelium with detached/desquamated strips of degenerated keratinocytes (Fig. 1a, b). Scattered lymphocytes were present within the lamina propria and no eosinophils were identified.

Fig. 1.

Fig. 1

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Irritant Contact Stomatitis Pattern #1. Case 1 A-B. a The oral mucosa in contact with Listerine™ mouth rinse is covered by a thin layer of detached parakeratin (H&E, × 100) (b) Detached strips of desquamated parakeratin (H&E, × 400). Case 2 C-F. c White plaques on the ventral tongue in contact with Listerine™ mouth rinse. d The oral mucosa is covered by thinly parakeratinized stratified squamous epithelium with detached strips of parakeratin (H&E, × 20). e Detached strips of desquamated parakeratin and keratinocytes (H&E, × 600). f Complete resolution of the lesions after discontinuing Listerine™ mouth rinse

Case 2

A 72-year-old female presented with white homogenous plaques on the ventral tongue in contact with Listerine™ mouthwash (Fig. 1c). The biopsy revealed minimally parakeratinized stratified squamous epithelium with desquamated strips of degenerated keratinocytes (Fig. 1d, e). The lesions resolved after the discontinuation of Listerine ™ mouth rinses (Fig. 1f).

Cases 3

A 37-year-old male presented with a white, fissured plaque on the left maxillary vestibule in contact with smokeless tobacco. The biopsy revealed stratified squamous epithelium with a moderately thick layer of parakeratin. There was a demarcated, superficial layer of edematous keratinocytes exhibiting karyopyknosis and minimal inflammation within the lamina propria (Fig. 2a, b).

Fig. 2.

Fig. 2

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Irritant Contact Stomatitis Pattern #2. Case 3 (a, b). a The oral mucosa in contact with smokeless tobacco shows a thick layer of edematous and degenerated keratinocytes that is sharply demarcated (H&E, × 40). b Keratinocytes exhibit karyopyknosis (H&E, × 200). Case 4 (c, d). c The oral mucosa in contact with chewing gum exhibits a thick layer of edematous and degenerated keratinocytes that is sharply demarcated (H&E, × 40). d Superficial keratinocytes exhibit parakeratin chevrons and karyopyknosis (H&E, × 200). Case 5 (e, f). e The oral mucosa in contact with Nicorette™ lozenges exhibits thin parakeratosis and a thick layer of edematous and degenerated keratinocytes that is sharply demarcated (H&E, × 40). f Superficial keratinocytes exhibit parakeratin chevrons and karyopyknosis (H&E, × 200)

Case 4

A 58-year-old female presented with a well-demarcated white plaque on the right lateral border of the tongue in contact with chewing gum. She chews one pack of gum of varying flavors every day and holds the gum between her tongue and the lower anterior lingual gingiva; she never used smokeless tobacco. The biopsy revealed thinly parakeratotic stratified squamous epithelium and a demarcated superficial layer of edematous keratinocytes exhibiting parakeratin chevrons and karyopyknosis (Fig. 2c, d). There was insignificant inflammation within the lamina propria. These findings are similar to those seen in Case 3, caused by smokeless tobacco.

Case 5

A 46-year-old-female presented with a white plaque on the left lateroventral tongue that had been in contact with Nicorette™ lozenges for the past two years. The biopsy revealed thinly parakeratinized stratified squamous epithelium exhibiting acanthosis and demarcated superficial layer of edematous keratinocytes exhibiting parakeratin chevrons and karyopyknosis. There was minimal inflammation within the lamina propria (Fig. 2e, f). These findings are similar to those caused by smokeless tobacco (Case 3) and chewing gum (Case 4).

Case 6

A 73-year-old female presented with white plaques on the right ventral tongue. She reported placing her daily dose of Tums™ at this site. The biopsy revealed coagulative necrosis of three quarters of the epithelium with spongiosis, spongiotic pustules and microabscesses in the epithelium. A mild lymphocytic infiltrate was present within the lamina propria (Fig. 3a, b).

Fig. 3.

Fig. 3

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Irritant Contact Stomatitis Pattern #3. Case 6 (a, b). a The oral mucosa in contact with Tums™ exhibits coagulative necrosis and scattered lymphocytes within the lamina propria (H&E, × 40). b There are spongiotic pustules, intraepithelial microabscesses and intraepithelial clefting (H&E, × 400)

Contact Hypersensitivity Stomatitis

Six cases of CHS exhibited two distinct histological patterns as follows: (1) sub-epithelial dense polyclonal plasma cell infiltrate (plasma cell stomatitis) and (2) a lymphohistiocytic infiltrate with/out non-necrotizing granulomatous inflammation at the interface often in a peri- and para-vascular location (Table 1).

Case 7

A 66-year-old male presented with generalized erythema of the maxillary and mandibular facial gingiva and right buccal mucosa, diffuse erythema and some fissuring of the left buccal mucosa and ulceration of the left mandibular buccal vestibule (Fig. 4a, b). He had been using Sensodyne Extra-Whitening™ toothpaste on the advice of his dentist who had professionally bleached his teeth after placing the crowns several months ago. After replacing Sensodyne Extra-Whitening™ with Nature's Gate™ peppermint toothpaste, the patient’s lesions resolved during a 4-month follow-up without any topical steroid therapy (Fig. 4c, d). Biopsy of the left buccal mucosa revealed parakeratinized stratified squamous epithelium exhibiting spongiosis, leukocyte exocytosis and sheets of polyclonal plasma cells within the lamina propria admixed with lymphocytes and scattered eosinophils typical for plasma cell stomatitis (Fig. 5a–d). The periodic acid Schiff stain with diastase digestion and the Warthin-Starry stain did not reveal the presence of organisms.

Fig. 4.

Fig. 4

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Oral mucosa in contact with Sensodyne Extra-Whitening™ toothpaste (Case 7). a There is generalized, marked erythema of the maxillary and mandibular facial gingiva. b There is diffuse erythema of the left buccal mucosa and vestibule with linear ulceration. c At the four-month follow-up, there is resolution of erythema of the gingiva and d left buccal mucosa and mandibular buccal vestibule on discontinuation of Sensodyne Extra-Whitening™ toothpaste

Fig. 5.

Fig. 5

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Contact Hypersensitivity Stomatitis Pattern #1 (Case 7). a There are sheets of plasma cells within the lamina propria typical for plasma cell stomatitis (H&E, × 40). b The overlying epithelium is atrophic and exhibits spongiosis and leukocyte exocytosis (H&E, × 200) and there are back-to-back plasma cells admixed with eosinophils (inset, H&E, × 400). c Polyclonal plasma cells show positivity for kappa (ISH, × 40) and d lambda light chains (ISH, × 40)

Case 8

A 68-year-old female presented with a keratotic plaque measuring 0.5 cm x 0.3 cm on the hard palatal mucosa associated with tooth #13 that had been in contact with Listerine Fresh Breath Strips™. She reported a habit of placing and holding these fresh breath strips at that site 5–6 times a day for many months. The biopsy revealed hyperkeratotic stratified squamous epithelium exhibiting acanthosis, mild spongiosis, leukocyte exocytosis, colloid bodies and degeneration of basal cells. Focal clusters of monocytes were also present within the epithelium. A mild lymphohistiocytic infiltrate and subtle non-necrotizing granuloma was noted within the superficial lamina propria (Fig. 6a, b). Neither eosinophils nor refractile foreign material was identified.

Fig. 6.

Fig. 6

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Contact Hypersensitivity Stomatitis Pattern #2, Type 1. Case 8 (a, b). a The oral lesion in contact with Listerine Fresh Breath Strips™ shows hyperkeratosis and a mild lymphohistiocytic infiltrate within the lamina propria (H&E, × 40). b Focal clusters of mononuclear monocytes (small arrows) are present within the epithelium and subtle non-necrotizing granulomas (big arrow) are noted in the superficial lamina propria (H&E, × 200). Case 9 (c–f). c, d Generalized erythema of the maxillary and mandibular facial gingiva in contact with Crest Pro-Health™ toothpaste. Courtesy of Dr. Mark Zajkowski, private practice, Portland, ME. e The oral mucosa is covered by nonkeratinized stratified squamous epithelium exhibiting acanthosis, spongiosis and leukocyte exocytosis (H&E, × 40). f A dense lymphohistiocytic band is present at the interface with the formation of subtle granulomas (H&E, × 200)

Case 9

A 20-year-old female presented with a diffuse mild erythema of the maxillary facial gingiva and marked erythema of the mandibular facial gingiva with sensitivity upon brushing (Fig. 6c, d). She had been using Crest Pro-Health™ toothpaste for several years. There was no history of use of chewing gum or candies. The biopsy revealed nonkeratinized stratified squamous epithelium exhibiting acanthosis, spongiosis and leukocyte exocytosis. There was a moderately intense lymphohistiocytic infiltrate at the interface with the presence of subtle non-necrotizing granulomas in the absence of refractile or otherwise identifiable foreign material (Fig. 6e, f).

Case 10

A 62-year-old female presented with a white plaque on the right buccal mucosa near the lip commissure measuring 1 cm x 0.5 cm which had been in contact with Trident™ cinnamon-flavored chewing gum; she chewed approximately 10 packets of gum per day. The biopsy showed parakeratinized stratified squamous epithelium with acanthosis, mild spongiosis and leukocyte exocytosis with preservation of the basal cells. A mild lymphohistiocytic infiltrate was present at the interface and there were deep peri- and para-vascular nodular lymphohistiocytic infiltrates (Fig. 7a, b). Eosinophils and foreign material were not identified.

Fig. 7.

Fig. 7

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Contact Hypersensitivity Stomatitis Pattern #2, Type 2. Case 10 (a, b). a The oral mucosa in contact with Trident™ cinnamon-flavored chewing gum exhibits a mild lymphohistiocytic band at the interface (H&E, × 40). b Peri- and para-vascular lymphohistiocytic nodules are noted within the deep lamina propria (H&E, × 200). Case 11 (c, d). c The oral mucosa in contact with mint-flavored gum exhibits a moderate lymphohistiocytic band at the interface and deep peri- and para-vascular nodular lymphohistiocytic infiltrates (H&E, × 40) with focal germinal center formation (inset, H&E, × 200). d There are rare eosinophils (arrow) within the lamina propria (H&E, × 400)

Case 11

A 64-year-old female presented with a left maxillary vestibular lesion that has been in contact with mint-flavored chewing gum. The biopsy revealed thinly parakeratinized stratified squamous epithelium with acanthosis, mild spongiosis and leukocyte exocytosis. A diffuse lymphohistiocytic infiltrate with rare eosinophils was present within the connective tissue. There were also deep peri- and paravascular nodular lymphohistiocytic infiltrates with germinal centers, admixed with many plasma cells and occasional eosinophils (Fig. 7c, d). Foreign material was not identified.

Case 12

A 46-year-old female presented with a white plaque on the right buccal mucosa in contact with Nicorette™ gum. The biopsy revealed parakeratinized stratified squamous epithelium exhibiting acanthosis, mild spongiosis and leukocyte exocytosis. There was a focal mild lymphocytic band at the interface and non-necrotizing peri- and para-vascular granulomatous inflammation within the deep lamina propria (Fig. 8a, b). The acid-fast bacillus, Fite and Gomori methenamine silver stains were negative for microorganisms, and foreign material was not identified.

Fig. 8.

Fig. 8

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Contact Hypersensitivity Stomatitis Pattern #2, Type 3. Case 10 (a, b). a The oral mucosa in contact with Nicorette™ gum exhibits a mild lymphohistiocytic band at the interface (H&E, 40X). b Peri- and para-vascular lymphoid nodules containing non-necrotizing granulomas are noted within the lamina propria (H&E, 200X)

Discussion

The oral cavity is a site susceptible to ICS and CHS because it is frequently in contact with potentially irritant or allergic substances either in food, chewing gum, candies or dentifrices. ICS is similar to irritant contact dermatitis with more severe lesions showing a localized inflammatory process after a single, repeated or prolonged exposure to physical or chemical irritants [3, 4]. CHS, on the other hand, is akin to contact hypersensitivity dermatitis, which is a T-cell mediated, delayed type IV hypersensitivity reaction in response to a second or successive exposure of contact allergens [1, 2].

Clinical findings of ICS in the literature include mucosal desquamation, edema and white plaques [3–5, 7, 13]. We report five cases of ICS that presented as white plaques and one case that exhibited mucosal sloughing. Irritants that are more caustic in nature with longer mucosal contact time lead to more prominent surface damage, inflammation and sometimes ulcers [14]. Some examples of oral irritants include medications such as aspirin which causes ulceration and cocaine which can cause necrotizing acute periodontitis-like lesions and hard palatal perforation [4, 7, 15–17]. The irritants in these cases namely Listerine™ mouth rinses, smokeless tobacco, varying flavors of chewing gum, Nicorette™ lozenges and Tums™ were, fortunately, not caustic enough to cause ulcers. Other oral irritants include chemicals found in oral hygienic products such as sodium lauryl sulfate (SLS), alcohol, triclosan and tetrasodium and tetrapotassium pyrophosphate [18–20]. Even garlic has been known to cause mucosal ulcerations when directly applied to the mucosa for a protracted period of time [7].

These biopsies of ICS exhibit one of these three distinct histopathological patterns. The first pattern is characterized by detached strips of degenerated, desquamated keratinocytes.[18, 19, 21] One common cause of oral mucosal desquamation is dentifrice containing synthetic detergents (such as SLS) and/or antimicrobial agents (triclosan). A randomized crossover study showed 68% and 75% of the patients experienced oral mucosal sloughing when using toothpaste with 3% SLS/triclosan and 1.5% SLS, respectively [19]. However, alcohol can also cause mucosal desquamation. A study in patients with xerostomia demonstrated that after using Listerine™ mouth rinses for seven days, 10.5% of patients exhibit mucosal sloughing [22]. The ingredients in Listerine™ are eucalyptol 0.092%, menthol 0.042%, methyl salicylate 0.060%, thymol 0.064% and alcohol 26.9% [23]. Studies have shown that the prolonged exposure to mouth rinses containing essential oils, antiseptics, astringents along with a low pH directly damages the surface epithelium and manifests as epithelial sloughing [20, 22, 24]. Our cases suggest that this histological finding is not specific to SLS or triclosan and can be seen in other irritants such as those found in Listerine™ mouth rinses.

The second pattern in ICS is similar to those seen in smokeless tobacco lesions namely corrugated parakeratotic surface with parakeratin chevrons and epithelial acanthosis often with a demarcated band of edematous and degenerated keratinocytes [21]. Smokeless tobacco consists of a combination of tobacco, nicotine, benzo[a]pyrene, heavy metals, tobacco-associated nitrosamines, as well as variable additives and flavoring agents. It is considered an oral potentially malignant disorder by the World Health Organization[25], and the relative risk for developing carcinoma is 1.9 in long-term users [26]. Furthermore, early lesions in contact with smokeless tobacco are reversible and as such, likely ICS-related [26]. In support of this theory, two patients (Case 4 and 5) who were using varying flavors of chewing gum and Nicorette™ lozenges developed contact lesions that exhibited similar histological findings to our case of smokeless tobacco lesion (Case 3) supporting the theory such a pattern of ICS is a reversible contact irritation and not a mutated pre-cancerous condition. Most lesions generally show only thin parakeratin and it is likely the keratinocyte edema that produces the gray appearance of smokeless tobacco lesions (not the dense white keratosis of leukoplakia), similar to lesions of leukoedema. However, the leukoplakia that may develop within such lesions after decades of use are precancerous and do not generally regress even on cessation of the habit.

The third pattern of ICS is characterized by epithelial coagulative necrosis, spongiotic pustules and intraepithelial microabscesses. These histological findings seen in Case 6 in contact with Tums™ are similar to those seen in its cutaneous counterpart, irritant contact dermatitis and has been well studied by Lachapelle [27]. Irritant contact dermatitis is characterized by epidermal necrosis, pustule formation and acantholysis with rare to no eosinophils identified within the epithelium or connective tissue [27]. The active ingredient of Tums™ is calcium carbonate, which has a pH of 9. Similarly, studies have also shown that aspirin (pH of 3.5) and garlic (pH of 13) may lead to chemical burns, which show similar histological patterns to ICS [3, 4, 7].

Similar to ICS, CHS may manifest as areas of mucosal sensitivity and painful erythema, and the continual exposure to a contactant may lead to vesicles, erosions, ulcers, white plaques or any combination of such findings, which are indistinguishable from those of ICS [28]. Our cases of CHS clinically presented as diffuse erythema, ulceration, and white plaques. These symptoms resolve with the removal of the causative contactant and patients often exhibit positive patch test studies for specific allergens [29]. Common contactants include dentifrice flavoring agents (cinnamic aldehyde and peppermint essential oil), preservatives (gallates and benzoic acid), and dental materials (mercury, gold and nickel) [30–32]. Once the diagnosis is established with a biopsy, identification and elimination of the contactant leads to resolution.

The first pattern of CHS (and one that has been well-studied) is that of plasma cell stomatitis, which is characterized by a sheets of polyclonal plasma cells that fill the lamina propria. Plasma cell stomatitis represents a hypersensitivity reaction to contactants such as flavorings within chewing gum, candies and dentifrices [33, 34]. It is sometimes called plasma cell peri-orifical mucositis and can affect the lip, larynx, vulva and penis (Zoon balanitis) [35–37]. Persistent contact to these allergens leads to generalized erythema of the gingiva or mucosa and surface ulcerations, and the elimination of contactants generally lead to resolution as seen in Case 7. The main ingredient of Sensodyne Extra-Whitening™ toothpaste is sodium tripolyphosphate, an anticariogenic agent with whitening properties, while the inactive ingredients include flavoring agents [38]. The lesions resolved without any topical anti-inflammatory therapy when the patient switched to an all-natural toothpaste. It is unclear if it is the sodium tripolyphosphate or flavoring agents that led to plasma cell stomatitis.

The second pattern of CHS includes a histopathological spectrum of lymphohistiocytic infiltrate at the interface and/or peri- and para-vascular granulomatous inflammation with or without non-necrotizing granulomas. This pattern has been well-documented in CHS to cinnamic aldehyde and is characterized by lymphohistiocytic inflammation at the interface and deep peri- and para-vascular lymphoid or lymphohistiocytic nodules [8, 10, 11, 28]. In our Cases 8 and 9, subtle nonnecrotizing granulomas were also seen, which is not surprising since granulomatous inflammation is a Type IV hypersensitivity reaction where activated macrophages admixed with lymphocytes play a crucial immune role in response to external stimuli [39]. This histological pattern is often diagnosed as lichenoid and granulomatous inflammation with an emphasis for clinical correlation. It is possible if not likely, that the lichenoid and granulomatous stomatitis described by Robinson et al.[40] on the upper lip mucosa represents a CHS. [41, 42]

Magro and Crowson[43] classified lichenoid and granulomatous dermatitis and this was modified by Hakeem et al.[44] as follows: (1) superficial loose or aggregated histiocytes with perivasculitis; (2) superficial loose or aggregated histiocytes without perivasculitis; (3) epithelioid giant cell granulomas with perivasculitis; and (4) epithelioid giant cell granulomas without perivasculitis. Our cases of CHS did not show true vasculitis characterized by endothelial damage, formation of thrombi and leukocytoclasia[45], but rather a peri- and/or para-vascular inflammatory infiltrate situated around vessels but not associated with endothelial damage [46]. We believe that there are three main patterns of lichenoid and granulomatous stomatitis: (1) lymphohistiocytic infiltrate at the interface with well-formed or loosely aggregated nonnecrotizing granulomas (Case 8 and 9); (2) lymphohistiocytic infiltrate at the interface with peri- and para-vascular lympho(-histiocytic) nodules (Cases 10–11); (3) lymphohistiocytic infiltrate at the interface with peri- and para-vascular lymphohistiocytic nodules containing nonnecrotizing granulomas (Case 12) (Table 2). Whether a lymphohistiocytic infiltrate at the interface with or without subtle granuloma formation (such as we often see in lichen planus) may represent CHS requires further exploration, importantly, with good clinical information.

Table 2.

Histological pattern #2 for cases of CHS: Interface lymphohistiocytic infiltrate + granulomatous inflammation

Type of pattern Case No Contactant Interface Lymphohistiocytic infiltrate Peri and paravascular granulomatous inflammation Well formed or loosely aggregates of non-necrotizing granulomas
1 8 List of Fresh Breath Stips™  + −  + 
9 Crest Pro-health™ toothpaste  +  −  + 
2 10 Trident ™ Cinnamon flavored chewing gum  +   +  −
11 Mint flavored chewing gum  +   +  −
3 12 Nicorette™ gum  +   +   + 
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The same contactant can cause an ICS or CHS reaction. For example, varying flavors of chewing gum may cause ICS (Case 4) or CHS (Cases 10 and 11). Similarly, Listerine™ mouth rinse (Case 1 and 2) caused contact desquamative stomatitis while Listerine Fresh Breath Strips™ (Case 8) resulted in granulomatous inflammation, emphasizing that one contactant may exhibit multiple histological patterns. Conversely, different contactants may elicit the same histological ICS or CHS pattern. For instance, tobacco (Case 3), varying flavors of chewing gum (Case 4) and Nicorette™ lozenges (Case 5) caused the same ICS histological pattern characterized by parakeratin chevrons and superficial keratinocyte edema that was sharply demarcated from underlying keratinocytes. Likewise, varying flavors of chewing gum as seen in CHS pattern II (Cases 10 and 11) may elicit the same histological findings caused by gold crowns with acrylic facings [28, 40]. Therefore, the common histological pattern elicited by cinnamic aldehyde-associated lichenoid mucositis may be seen in other contactants and should prompt the pathologist to inquire about other contactants besides cinnamon.

It is therefore important for pathologists to recognize key histologic patterns associated with ICS and CHS in order to assist clinicians in identifying contactants for patient management. In general, discontinuation of the culprit contactant results in resolution although topical steroid therapy is helpful in severe cases. However, if lesions do not resolve, patch testing may identify the specific inciting agent.

The limitation of this study is that the patients were not patch tested. The pros and cons of patch testing were discussed with the patients. However, they preferred habit cessation rather than patch testing since it would not necessarily change treatment or outcome and patch testing is generally considered not in and of itself necessarily diagnostic without correlation with clinical findings.

Conclusion

In these 12 cases, we demonstrate that ICS and CHS exhibit distinct histological patterns, where various contactants or even substances with very high pH may cause mucosal lesions that can exhibit similar histological features, or one contactant may elicit different histopathological patterns of inflammation. We note three patterns of ICS and propose three histopathologic patterns of CHS that are lichenoid and granulomatous. These different histological patterns may assist clinicians in recognizing potential contactants that contribute to such inflammatory mucosal lesions (Table 1).

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declarations

Conflict of interest

The authors deny any conflict of interest.

Ethical Approval

This case series study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Human Research Committee (IRB) of Brigham and Women’s Hospital approved this study (2017-P100).

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  • 1.Kaplan DH, Igyarto BZ, Gaspari AA. Early immune events in the induction of allergic contact dermatitis. Nat Rev Immunol. 2012;12:114–124. doi: 10.1038/nri3150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Feller L, Wood NH, Khammissa RA, Lemmer J. Review: allergic contact stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;123:559–565. doi: 10.1016/j.oooo.2017.02.007. [DOI] [PubMed] [Google Scholar]
  • 3.Ale IS, Maibach HI. Irritant contact dermatitis. Rev Environ Health. 2014;29:195–206. doi: 10.1515/reveh-2014-0060. [DOI] [PubMed] [Google Scholar]
  • 4.Rawal SY, Claman LJ, Kalmar JR, Tatakis DN. Traumatic lesions of the gingiva: a case series. J Periodontol. 2004;75:762–769. doi: 10.1902/jop.2004.75.5.762. [DOI] [PubMed] [Google Scholar]
  • 5.Mathias CG, Maibach HI. Dermatotoxicology monographs I. Cutaneous irritation: factors influencing the response to irritants. Clin Toxicol. 1978;13:333–346. doi: 10.3109/15563657808988241. [DOI] [PubMed] [Google Scholar]
  • 6.Cifuentes M, Davari P, Rogers RS., 3rd Contact stomatitis. Clin Dermatol. 2017;35:435–440. doi: 10.1016/j.clindermatol.2017.06.007. [DOI] [PubMed] [Google Scholar]
  • 7.Bagga S, Thomas BS, Bhat M. Garlic burn as self-inflicted mucosal injury–a case report and review of the literature. Quintessence Int. 2008;39:491–494. [PubMed] [Google Scholar]
  • 8.Allen CM, Blozis GG. Oral mucosal reactions to cinnamon-flavored chewing gum. J Am Dent Assoc. 1988;116:664–667. doi: 10.14219/jada.archive.1988.0003. [DOI] [PubMed] [Google Scholar]
  • 9.Hoskyn J, Guin JD. Contact allergy to cinnamal in a patient with oral lichen planus. Contact Dermatitis. 2005;52:160–161. doi: 10.1111/j.0105-1873.2005.0548b.x. [DOI] [PubMed] [Google Scholar]
  • 10.Bousquet PJ, Guillot B, Guilhou JJ, Raison-Peyron N. A stomatitis due to artificial cinnamon-flavored chewing gum. Arch Dermatol. 2005;141:1466–1467. doi: 10.1001/archderm.141.11.1466-c. [DOI] [PubMed] [Google Scholar]
  • 11.Kind F, Scherer K, Bircher AJ. Allergic contact stomatitis to cinnamon in chewing gum mistaken as facial angioedema. Allergy. 2010;65:276–277. doi: 10.1111/j.1398-9995.2009.02152.x. [DOI] [PubMed] [Google Scholar]
  • 12.Mowad CM. Contact dermatitis: practice gaps and challenges. Dermatol Clin. 2016;34:263–267. doi: 10.1016/j.det.2016.02.010. [DOI] [PubMed] [Google Scholar]
  • 13.Vucicevic Boras V, Brailo V, Andabak Rogulj A, Vidovic Juras D, Gabric D, Vrdoljak DV. Oral adverse reactions caused by over-the-counter oral agents. Case Rep Dent. 2015;2015:196292. doi: 10.1155/2015/196292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Davis CC, Squier CA, Lilly GE. Irritant contact stomatitis: a review of the condition. J Periodontol. 1998;69:620–631. doi: 10.1902/jop.1998.69.6.620. [DOI] [PubMed] [Google Scholar]
  • 15.Kapila YL, Kashani H. Cocaine-associated rapid gingival recession and dental erosion. A case report. J Periodontol. 1997;68:485–488. doi: 10.1902/jop.1997.68.5.485. [DOI] [PubMed] [Google Scholar]
  • 16.Blanksma CJ, Brand HS. Cocaine abuse: orofacial manifestations and implications for dental treatment. Int Dent J. 2005;55:365–369. doi: 10.1111/j.1875-595x.2005.tb00047.x. [DOI] [PubMed] [Google Scholar]
  • 17.Gandara-Rey JM, Diniz-Freitas M, Gandara-Vila P, Blanco-Carrion A, Garcia-Garcia A. Lesions of the oral mucosa in cocaine users who apply the drug topically. Med Oral. 2002;7:103–107. [PubMed] [Google Scholar]
  • 18.Kowitz G, Jacobson J, Meng Z, Lucatorto F. The effects of tartar-control toothpaste on the oral soft tissues. Oral Surg Oral Med Oral Pathol. 1990;70:529–536. doi: 10.1016/0030-4220(90)90226-i. [DOI] [PubMed] [Google Scholar]
  • 19.Skaare A, Eide G, Herlofson B, Barkvoll P. The effect of toothpaste containing triclosan on oral mucosal desquamation. A model study. J Clin Periodontol. 1996;23:1100–1103. doi: 10.1111/j.1600-051x.1996.tb01810.x. [DOI] [PubMed] [Google Scholar]
  • 20.Perez-Lopez D, Varela-Centelles P, Garcia-Pola MJ, Castelo-Baz P, Garcia-Caballero L, Seoane-Romero JM. Oral mucosal peeling related to dentifrices and mouthwashes: a systematic review. Med Oral Patol Oral Cir Bucal. 2019;24:e452–e460. doi: 10.4317/medoral.22939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Muller S. Frictional keratosis, contact keratosis and smokeless tobacco keratosis: features of reactive white lesions of the oral mucosa. Head Neck Pathol. 2019;13:16–24. doi: 10.1007/s12105-018-0986-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Fischman SL, Aguirre A, Charles CH. Use of essential oil-containing mouth rinses by xerostomic individuals: determination of potential for oral mucosal irritation. Am J Dent. 2004;17:23–26. [PubMed] [Google Scholar]
  • 23.Osso D, Kanani N. Antiseptic mouth rinses: an update on comparative effectiveness, risks and recommendations. J Dent Hyg. 2013;87:10–18. [PubMed] [Google Scholar]
  • 24.Kuyama K, Yamamoto H. A study of effects of mouthwash on the human oral mucosae: with special references to sites, sex differences and smoking. J Nihon Univ Sch Dent. 1997;39:202–210. doi: 10.2334/josnusd1959.39.202. [DOI] [PubMed] [Google Scholar]
  • 25.Kumar A, Bhartiya D, Kaur J, et al. Regulation of toxic contents of smokeless tobacco products. Indian J Med Res. 2018;148:14–24. doi: 10.4103/ijmr.IJMR_2025_17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Rodu B, Jansson C. Smokeless tobacco and oral cancer: a review of the risks and determinants. Crit Rev Oral Biol Med. 2004;15:252–263. doi: 10.1177/154411130401500502. [DOI] [PubMed] [Google Scholar]
  • 27.Lachapelle JM. Comparative histopathology of allergic and irritant patch test reactions in man. Current concepts and new prospects. Arch Belg Dermatol Syphiligr. 1973;29:83–92. [PubMed] [Google Scholar]
  • 28.De Rossi SS, Greenberg MS. Intraoral contact allergy: a literature review and case reports. J Am Dent Assoc. 1998;129:1435–1441. doi: 10.14219/jada.archive.1998.0078. [DOI] [PubMed] [Google Scholar]
  • 29.Suter VG, Warnakulasuriya S. The role of patch testing in the management of oral lichenoid reactions. J Oral Pathol Med. 2016;45:48–57. doi: 10.1111/jop.12328. [DOI] [PubMed] [Google Scholar]
  • 30.Minciullo PL, Paolino G, Vacca M, Gangemi S, Nettis E. Unmet diagnostic needs in contact oral mucosal allergies. Clin Mol Allergy. 2016;14:10. doi: 10.1186/s12948-016-0047-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Khamaysi Z, Bergman R, Weltfriend S. Positive patch test reactions to allergens of the dental series and the relation to the clinical presentations. Contact Dermatitis. 2006;55:216–218. doi: 10.1111/j.1600-0536.2006.00905.x. [DOI] [PubMed] [Google Scholar]
  • 32.Reinhart JP, Stoopler ET, Crawford GH. Oral Hypersensitivity Reactions. Dermatol Clin. 2020;38:467–476. doi: 10.1016/j.det.2020.05.007. [DOI] [PubMed] [Google Scholar]
  • 33.Silverman S, Jr, Lozada F. An epilogue to plasma-cell gingivostomatitis (allergic gingivostamtitis) Oral Surg Oral Med Oral Pathol. 1977;43:211–217. doi: 10.1016/0030-4220(77)90158-x. [DOI] [PubMed] [Google Scholar]
  • 34.Solomon LW, Wein RO, Rosenwald I, Laver N. Plasma cell mucositis of the oral cavity: report of a case and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106:853–860. doi: 10.1016/j.tripleo.2008.08.016. [DOI] [PubMed] [Google Scholar]
  • 35.Lee JY, Kim KH, Hahm JE, et al. Plasma cell cheilitis: a clinicopathological and immunohistochemical study of 13 cases. Ann Dermatol. 2017;29:536–542. doi: 10.5021/ad.2017.29.5.536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Smith JGF, Smith CP, Leyden PJ. Plasma cell mucositis of the larynx. Clin Case Rep. 2018;6:1761–1764. doi: 10.1002/ccr3.1726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Bharatia PR, Pradhan AM, Zawar VP. Plasma cell vulvitis. Indian J Sex Transm Dis AIDS. 2015;36:185–187. doi: 10.4103/2589-0557.167172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Shellis RP, Addy M, Rees GD. In vitro studies on the effect of sodium tripolyphosphate on the interactions of stain and salivary protein with hydroxyapatite. J Dent. 2005;33:313–324. doi: 10.1016/j.jdent.2004.09.006. [DOI] [PubMed] [Google Scholar]
  • 39.Asai J. What is new in the histogenesis of granulomatous skin diseases? J Dermatol. 2017;44:297–303. doi: 10.1111/1346-8138.13662. [DOI] [PubMed] [Google Scholar]
  • 40.Robinson CM, Oxley JD, Weir J, Eveson JW. Lichenoid and granulomatous stomatitis: an entity or a non-specific inflammatory process? J Oral Pathol Med. 2006;35:262–267. doi: 10.1111/j.1600-0714.2006.00419.x. [DOI] [PubMed] [Google Scholar]
  • 41.Thornhill MH, Sankar V, Xu XJ, et al. The role of histopathological characteristics in distinguishing amalgam-associated oral lichenoid reactions and oral lichen planus. J Oral Pathol Med. 2006;35:233–240. doi: 10.1111/j.1600-0714.2006.00406.x. [DOI] [PubMed] [Google Scholar]
  • 42.Sugerman PB, Savage NW, Walsh LJ, et al. The pathogenesis of oral lichen planus. Crit Rev Oral Biol Med. 2002;13:350–365. doi: 10.1177/154411130201300405. [DOI] [PubMed] [Google Scholar]
  • 43.Magro CM, Crowson AN. Lichenoid and granulomatous dermatitis. Int J Dermatol. 2000;39:126–133. doi: 10.1046/j.1365-4362.2000.00868.x. [DOI] [PubMed] [Google Scholar]
  • 44.Hakeem A, Bhattacharyya I, Aljabri M, et al. Lichenoid reaction with granulomatous stomatitis: a retrospective histologic study of 47 patients. J Oral Pathol Med. 2019;48(9):846–854. doi: 10.1111/jop.12918. [DOI] [PubMed] [Google Scholar]
  • 45.Carlson JA. The histological assessment of cutaneous vasculitis. Histopathology. 2010;56:3–23. doi: 10.1111/j.1365-2559.2009.03443.x. [DOI] [PubMed] [Google Scholar]
  • 46.Buchner A, Hansen LS. Amalgam pigmentation (amalgam tattoo) of the oral mucosa. A clinicopathologic study of 268 cases. Oral Surg Oral Med Oral Pathol. 1980;49:139–147. doi: 10.1016/0030-4220(80)90306-0. [DOI] [PubMed] [Google Scholar]

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