Plasma cell gingivitis (PCG) is an inflammatory condition that affects the gingival mucosa of the oral cavity. It is characterized by polyclonal dense plasma cell infiltrate in the connective tissue. Lesions do not respond to prophylactic treatment. Etiology is most likely hypersensitivity to certain antigens (eg, toothpastes, oral rinses, chewing gums, spices). Differential diagnosis of PCG includes reactive, granulomatous, and neoplastic lesions. The diagnostic workup is based on patient’s history and the clinicopathologic correlation to rule out mimics of PCG. Dermatologic patch test may be indicated in chronic conditions to identify the allergen.
Key points
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Plasma cell gingivitis is a distinct, benign inflammatory oral condition most often limited to the free and attached gingiva.
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Clinicopathologic correlation is required for diagnosis.
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The line of treatment depends on the severity of symptoms and esthetic concerns.
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Management can vary from identifying and eliminating the offending allergen to topical or systemic steroids.
Plasma cell gingivitis
Plasma cell gingivitis (PCG) is a rare inflammatory oral condition characterized by a polyclonal proliferation of plasma cells in the subepithelial gingival tissue. PCG is also known by a variety of other names such as atypical gingivostomatitis, plasmacytosis, idiopathic gingivostomatitis, and allergic gingivostomatitis. Although etiopathogeneses remain unknown, several factors especially hypersensitivity to certain antigens (eg, toothpastes, oral rinses, chewing gums, spices) have been considered to play a crucial role. However, most of these lesions are considered to be idiopathic.
Clinical Features of Plasma Cell Gingivitis and Diagnostic Workup
PCG can affect any age and both genders with a higher prevalence in women. Clinically, it may involve any area of the mouth, with most cases presenting as lesions of rapid onset in the free and attached gingiva. Specifically, it can appear as localized or diffuse edematous, and erythematous gingival tissues which can easily bleed, lose its normal stippling, with or without surface ulcerations ( Fig. 1 ). Usually, the lesions are asymptomatic but in some cases can cause pain or even a burning sensation. A characteristic of the disease is the absence of desquamation of the gingiva and a negative Nikolsky sign, which is helpful in differentiating it from other vesiculobullous diseases. White striations characteristic of lichenoid lesions is also usually absent. Other rare clinical presentations have been reported including those with a white keratotic component, papillomatous, cobblestone, nodular, or velvety appearance. Diagnostic workup is based on the patient’s history and clinicopathologic correlation, whereas a full blood count (leukemia), erythrocyte sedimentation rate (lupus, infection, inflammation), serum angiotensin converting enzyme (s-ACE) (sarcoidosis), antineutrophil cytoplasmic antibodies (granulomatosis with polyangiitis), and dermatologic patch testing for contact allergens , can be indicated to rule out the many mimics of PCG. Nonetheless, the diagnosis must be histologically confirmed.
Histopathologic Features of Plasma Cell Gingivitis
Microscopically, PCG consists of a dense plasma cell infiltrate in the subepithelial connective tissue ( Fig. 2 ). Epithelium has been described as psoriasiform , and epithelial hyperplasia with elongated rete ridges, spongiosis, and loss of normal keratinization or papillary thinning and dyskeratosis can be also seen. The stroma can be predominantly vascular. The histopathologic differential diagnosis includes monoclonal neoplastic processes like plasmacytoma, multiple myeloma (MM), Waldenström macroglobulinemia, and lymphoma , , Immunohistochemistry and/or in situ hybridization of kappa (κ) and lambda (λ) immunoglobulin (Ig) light chains ( Fig. 3 ), along with IgG, IgA, and IgM immunoglobulins, should demonstrate the polyclonal origin of the plasma cell infiltrate to confirm the diagnosis of PCG. Special stains for infectious agents should be negative. The presence of large numbers of plasma cells also seen in chronic inflammatory periodontal diseases can sometimes cause difficulty in distinguishing ordinary gingival inflammation from PCG. The presence of mixed inflammatory cells and the clinical correlation with the chronic nature of the periodontal disease can help distinguish it from PCG.
Management of Plasma Cell Gingivitis
The management of PCG can be a challenge. There are no specific treatment protocols and management lacks international consensus about drug classes and regimens, often resulting in poor clinical outcome. , Generally, asymptomatic lesions may not require treatment; however, for symptomatic lesions or those causing esthetic concern, treatment is usually required. The clinician’s first concern is to elicit from the patient’s history possible exposure to allergens or causative factors (eg, chewing gums, certain food, cosmetics, and oral hygiene products). , , If temporal relation can be identified with the introduction of a specific agent, the lesions usually subside on removal of the causative factor. Although PCG does not respond to plaque control, attention should still be paid to local factors and mouthwash use, in order to reduce immunologic cell-mediated and cytokine-mediated responses that can complicate recovery. Treatment is usually symptom-based, with topical corticosteroids (0.05% clobetasol propionate, dexamethasone 0.5 mg/5 mL, fluocinonide 0.05%, triamcinolone acetonide 0.1%) , ( Fig. 4 ). Response to antihistaminic chlorpheniramine maleate has been also reported. For persistent cases, systemic steroids, immunomodulators, and sometimes antibiotics (doxycycline and 2% fusidic acid) have been elected. , PCG is generally an innocuous condition with no evidence of malignant transformation. Surgical excision and laser ablation have been reported to treat the condition, but the PCG lesions are usually recurrent if the causative factor was not identified or avoided.
Clinical differential diagnosis
The oral clinical differential diagnosis of the condition is very important as it can mimic a wide range of other entities such as medication-related gingival lesions, granulomatous lesions (foreign body gingivitis, sarcoidosis, and Crohn’s disease), reactive lesions like spongiotic gingival hyperplasia, and less common, ligneous gingivitis. , , ,
Medication-Related Gingival Lesions
Administration of several medications due to an underlying systemic disease can cause lesions similar to PCG. Chemotherapy can cause erythematous and ulcerative lesions of the oral cavity that can involve the gingiva. Phenytoin, calcineurin inhibitors (cyclosporine), calcium-channel blockers (nifedipine, amlodipine, and oxodipine), and oral contraceptives are agents that most commonly cause drug-induced gingival enlargement. , These lesions usually manifest as firm enlargement of the gingiva. The swelling typically starts 1 to 4 months after drug administration in the interdental gingiva and progresses to involve the marginal and attached gingivae. The enlargement is usually diffuse and is more severe in the maxillary and mandibular anterior region. In some cases, the gingiva is edematous and erythematous and may mimic PCG. Histopathologically, the lesions consist of epithelial hyperplasia, long rete ridges, hyperplastic fibrous and collagenous connective tissue, and chronic inflammation that lack the predominant plasma cell component of PCG. Diagnosis is based on the patient’s history, clinical examination, and the bulky fibrous overgrowth that is usually easily identified as medication-induced gingival hyperplasia not PCG. The putative drug should be withdrawn if this is possible by the treating physician, as discontinuation of the drug leads to inhibition of the progression of the disease and even regression of the gingival hyperplasia. Gingivectomy may be helpful in cases of intense enlargements and careful oral hygiene remains an important parameter.
Foreign Body Gingivitis
Foreign body gingivitis is a chronic inflammatory disease involving the marginal and/or attached gingiva and is due to the immune-mediated reaction against embedded foreign body material. Clinically, the disease appears as solitary or multiple red or red and white lesions, sometimes resembling erosions, and frequently the interdental papillae are also involved. , Sometimes, the patients complain about pain and swelling of the gingiva. The clinical appearance may mimic desquamative gingivitis and lichen planus, and only 50% of cases demonstrate granulomatous inflammation. Foreign body gingivitis develops more often in women (68%–84%) with a mean age of 48 year old. , Most of the times, the development of the lesions is preceded by microtrauma from dental restoration or prophylaxis. , Factors that have been associated with the development of foreign body gingivitis include amalgam, dental crown placement, dental prophylaxis, orthodontic treatment, and periodontal surgery. The lesions are often misdiagnosed as lichen planus or lichenoid reactions. Diagnosis is rendered by biopsy. Histologically, there is an intense band-like infiltrate of lymphocytes at the submucosal-epithelial interface and keratinocyte degeneration. In the connective tissue, microdeposits of foreign body particles can be discerned in histiocytes and multinucleated giant cells. The diagnostic criteria include the identification of foreign bodies in the connective tissue, where there is chronic inflammation and the presence of foreign bodies in at least two sequential tissue sections. The most common detected element is silica in 94% of cases. Silica is an ingredient of polishing paste and iatrogenic implantation of the foreign bodies may lead to silica granulomas. The second most frequent element is silicon followed by aluminum and titanium. Foreign body gingivitis is not correlated to plaque and calculus accumulation, and hygiene measures targeting plaque prevention have no effect. Furthermore, in contrast to oral lichen planus, steroid therapy shows no clinical improvement. , Surgical excision and gingival grafting are nowadays controversial and mostly applied in extreme cases. It is recommended to avoid air abrasion polishing in cases of the disease as further exacerbation is possible. Finishing and polishing of dental restorations close to soft tissues should be carried out carefully and in cases of gingival ulcerations or recent oral soft-tissue trauma, such dental treatment should be postponed after healing of the tissues.
Orofacial Granulomatosis
Orofacial granulomatosis is a term used to describe the occurrence of granulomas in the orofacial region in the absence of any recognized systemic condition. Typically, orofacial granulomatosis presents as recurrent, persistent labial swellings, which result in enlargement of the lips. This condition may also be associated with oral ulceration, painless gingival overgrowth, and a cobblestone appearance of the buccal mucosa. Gingival manifestations are infrequently described in the literature and develop in 21% to 26% of patients. Gingival involvement presents as gingival enlargement, that is usually red in color, smooth and shiny, with loss of stippling. It can be either full-width or localized gingivitis. Biopsy is mandatory to establish diagnosis. Histopathologic examination reveals noncaseating granulomatous lesions and edema. Periodic Acid–Schiff, Grocott-Gomori’s methenamine silver, and acid-fast bacilli stains should be performed to rule out microbial infection, such as deep fungal infection, tuberculosis, and leprosy. In addition, examination of the specimen under polarized light microscopy should also be performed as to reveal any foreign body material. These histologic findings are indistinguishable from those of Crohn’s disease and may closely resemble sarcoidosis. However, clinical correlation helps in differentiating these conditions. ,
Sarcoidosis
Sarcoidosis is a multiorgan disorder of unknown etiology which usually presents with pulmonary infiltration and hilar lymphadenopathy. Involvement of the eyes, skin, and salivary glands is relatively common. Sarcoidosis rarely involves the oral cavity, although it has been reported to affect the buccal mucosa, tongue, lips, palate, floor of the mouth, mandible, and maxilla. Only 70 well-documented cases of oral sarcoidosis (with jaw bones and salivary glands involvement excluded) had been reported by 2013. Oral manifestations, even though they are rare, could be the first clinical sign of the disease. The gingiva was affected in only four cases. Gingival involvement in sarcoidosis may have many clinical presentations including painless enlargement with or without occasional ulceration, identical to orofacial granulomatosis, or solitary gingival swelling or as gingivitis/periodontitis with bleeding gums. Diagnostic clues in favor of sarcoidosis include the radiographic evidence of lung involvement, increased eosinophil count, and elevated serum ACE levels. In addition, histologic evidence consists of noncaseating granulomatous lesions, accompanied by epithelioid histiocytes rimmed with lymphocytes and scattered Langhans or foreign body-type giant cells. Many cases resolve spontaneously, but if treatment is necessary, it consists mainly of steroids and immune-modulating medications. ,
Crohn’s Disease
Crohn’s disease is a chronic granulomatous disorder of unknown etiology that affects mainly the ileum but may affect any part of the gastrointestinal tract, including the mouth. The pathogenesis of Crohn’s disease is related to the mucosal response to an environmental trigger that can be a bacterium or virus when a genetic predisposition is also present. Oral manifestations are the second most common extraintestinal manifestations of the disease and may precede, occur concurrently, or follow the onset of abdominal symptoms. Oral manifestations include multiple intraoral ulcerations similar to those of aphthous stomatitis, a cobblestone appearance of the buccal mucosa, diffuse firm enlargement of the lips, and reddish granulomatous enlargement of the gingiva. The most frequently affected areas are the lips, buccal mucosa, and gingiva. Orofacial manifestations are identical with those of orofacial granulomatosis, but they are usually associated with active intestinal disease. However, oral lesions precede the abdominal symptoms by months or years in almost 60%, especially in adolescents and young adults. Clinical diagnosis may be challenging if the lesions are subtle in early stages, or in the presence of predominantly gingival involvement. Gingivitis associated with Crohn’s disease may appear as gingival erythema or nodular swellings and ulcerations of the gingiva. Clinical differential diagnosis includes other causes of granulomatous gingivitis (foreign body gingivitis, sarcoidosis, and orofacial granulomatosis) and localized juvenile spongiotic gingival hyperplasia (LJSGH) in addition to PCG. Biopsy is necessary to establish diagnosis. Histopathologically, squamous epithelium may present with mild inflammatory cell exocytosis. The connective tissue is fibrous and shows infiltration of lymphocytes and plasma cells. Well-formed granulomas composed of epithelioid histiocytes, and lymphocytes are also seen. The granulomas in orofacial granulomatosis and oral Crohn’s disease are similar and the differential diagnosis between the two entities is quite difficult. Therefore, it is important to conduct a thorough clinical investigation to establish the final diagnosis.
Localized Juvenile Spongiotic Gingival Hyperplasia
LJSGH is a recently described benign condition in children and young adults. It was first described by Darling and colleagues, with the proposed term “juvenile spongiotic gingivitis.” The current term “Localized juvenile spongiotic gingival hyperplasia” was proposed by Chang and colleagues. However, recently other terms have been also suggested such as “spongiotic gingivitis with odontogenic metaplasia.” LJSGH appears as a solitary or multiple gingival lesion(s), with bright red color, on the attached gingiva, with subtly papillary or granular surface. , The lesions measure 0.2 to 1 cm, develop more often on the labial maxillary gingiva, and bleed easily. , The lesion is more common in Caucasians and there is no clear gender predominance. LJSGH most commonly appears in children younger than 18 years, age ranged from 5 to 39 year old. However, it is thought that the disease is more frequent at the first 5 years and at the second decade. Differential diagnosis includes pyogenic granuloma, Wegener granulomatosis, foreign body gingivitis, and hypersensitivity reactions including PCG. The etiopathogenesis is not clear. Many factors have been implicated including sex hormones, viruses, mouth breathing, orthodontic treatment, trauma, and developmental abnormalities but no causal relationship has been definitively established. , Microscopic and immunohistochemical similarities with the junctional epithelium have been reported. It has been proposed that the LJSGH results from “exteriorization” of the junctional epithelium that acquires features associated to the surface epithelium under the influence of local environmental stimuli. Histologically, there is subtle papillary epithelial hyperplasia, spongiosis, interconnecting rete pegs, and inflammatory cell exocytosis. The connective tissue is edematous, with vascular spaces and diffuse inflammatory infiltration. There is no amelioration with conservative oral hygiene measures or with topical steroids. The best treatment for solitary cases is excision with scalpel or laser. Recent studies showed that cryotherapy could also be efficient for multiple lesions. Recurrence occurs in 5.8% to 28.6% of solitary lesions and in 38.5% of multiple lesions. In some cases, spontaneous remission has been described, probably due to the elimination of a possible unknown causative factor.
Ligneous Gingivitis
Ligneous gingivitis is part of a clinical spectrum of an autosomal recessive condition, characterized by deficiency in plasminogen. Normally when plasminogen is converted to plasmin, it dissolves blood clots. On the deficiency of plasmin formation, blood clots tend to persist and grow and fibrin deposits form plaques and nodules that affect mucosal surfaces. The gingival lesions can present as patchy ulcerated papules and nodules with a very irregular surface. Conjunctival lesions of the upper eye lid that present as creamy yellowish to erythematous lesions are more common. Trauma to mucosal surfaces should be avoided to minimize fibrin accumulation. Topical or systemic plasminogen, or topical heparin combined with prednisone are used to treat the oral lesions. Surgical excision was also reported. The condition is indolent, with no increase in intravascular thrombosis and no effect on life expectancy.
Histologic differential diagnosis
Histologic differential diagnosis of PCG can include nonspecific chronic inflammatory conditions, such as chronic periodontitis that is characterized by connective tissue heavily infiltrated with plasma cells, as well as plasma cell neoplasms.
Plasmacytoma
Extramedullary plasmacytoma is a plasma cell neoplasm that develops in tissues other than bone. It is a relatively rare lesion, and it arises in 80% of the cases in nasopharynx, paranasal sinuses, and tonsils. The disease may affect the gingiva but is not that common. Gingival involvement was first described by Martinelli and Rulli as sessile gingival lesion which needs differential diagnosis from chronic gingivitis or PCG. The disease may appear as soft tissue mass that can be asymptomatic or demonstrates spontaneous bleeding. Histologically, the connective tissue is infiltrated by plasma cells in the form of sheets, small islands, or nodules. The plasma cells may vary in size and may be binucleated and multinucleated. These histologic features might not be enough to separate this lesion from PCG. However, the presence of Dutcher bodies and especially the identification of monoclonal Ig expression of these plasma cells are helpful in differential diagnosis. Immunohistochemistry is needed to confirm the monoclonality of the light chains that are expressed in plasmacytomas.
Multiple Myeloma
MM is a systematic disease and is included in malignant monoclonal gammopathies. It is a chronic, malignancy of plasma cells that presents mainly in the bone marrow, but it can also appear in other organs. The clones of plasma cells produce immunologically inactive monoclonal immunoglobulins or their subunits. MM represents 1% of all malignancies and 10% of hematological malignancies. , The disease develops mostly in patients over 50 year old, with a mean age of 60, and men, especially black men are more commonly involved. The etiopathogenesis of the neoplasm remains unknown. Clinical presentation is the result of the clonal production of plasma cells, the replacement of the normal cells in the bone marrow, and the presence of paraproteins in the urine. Clinical manifestations include bone pain, pathologic fractures, fatigue, amyloidosis, recurrent infections, bleeding predisposition, and nonspecific skin lesions. Diagnostic criteria of MM include the radiographic findings of mild bone resorption, multiple “punched out” radiolucent lesions, or osteoporotic lesions, the presence of atypical plasma cells discovered by bone marrow biopsy and abnormal Immunoglobulins in blood and urine. Oral manifestations develop in around 14% of the patients and include swelling (more often of the mandible), amyloidosis, “punched out” radiolucent lesions in the jaws, tooth mobility, bleeding, and ulcers of the oral mucosa. , Histologically, there is diffuse infiltration of plasma cells that can vary in appearance and are atypical. Immunohistochemistry is necessary to demonstrate the monoclonal plasma cell nature for the final diagnosis. ,
Leukemic Gingival Infiltration
Both the acute and chronic forms of all types of leukemia may have oral manifestations, but these features are more frequently seen in the acute phase. The oral complications of leukemia are due to the infiltration of leukemic cells that can manifest as gingival enlargement. The enlarged tissues are usually soft, shiny, erythematous, highly tender, and boggy in consistency that can bleed on palpation. The underlying thrombocytopenia can present as petechiae, ecchymosis, and hemorrhage. Neutropenia or impaired granulocyte function can present with increased predisposition to infection and mucosal ulceration. , Gingival involvement may be the initial presenting symptom in 5% of cases of acute myeloid leukemia. Dreizen and colleagues reported the highest gingival involvement in patients with acute monocytic leukemia (66.7%), followed by acute myelomonocytic leukemia (18.5%), and acute myeloblastic leukemia (3.7%). However, leukemic infiltration is not usually observed in edentulous mucosa. Poor oral hygiene and calculus accumulation may exacerbate the gingival inflammation and bleeding, complicating oral hygiene practice. The diagnosis of leukemia is made by a complete blood count showing pancytopenia and by identifying blast cells in the peripheral blood and bone marrow, whereas the identification of leukemic infiltration in biopsies of oral lesions may lead to diagnosis in undiscovered cases.
Lymphoma
The lymphomas are a group of malignant solid tumors involving cells of the lymphoreticular system. The most common presentation is painless, persistent enlargement of the lymph nodes, but extranodal lesions may also occur, especially in cases of non-Hodgkin lymphoma. Oral lesions as the initial manifestation of the disease are very rare, accounting for 0.1% to 5%. Oral non-Hodgkin lymphoma often mimics inflammatory disease and may present as non-tender gingival swelling with a smooth or ulcerated surface, a mass in the tongue or other oral mucosal sites or as an intraosseous lesion. Oral lesions may be the first manifestation of the disease, but the gingiva is one of the rarest sites for isolated cases (as oppose to palatal mucosa). Radiographic, hematologic, and histopathologic evaluation is required to establish the diagnosis.
Summary
PCG is a benign inflammatory lesion of the gingiva and less often also involving the oral mucosa. Diagnosis is confirmed on clinicopathologic correlation with identification of a dense polyclonal submucosal plasma cell infiltrate. Identifying and preventing exposure to the causative allergen should be always attempted, although it is not always possible as many cases are idiopathic. For chronic symptomatic cases, treatment is directed toward treating symptoms and can range from topical to systemic steroids.
Clinics care points
For diagnosis of plasma cell gingivitis, the following can be noticed:
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Sudden onset of erythematous and edematous lesions of the free and attached gingiva.
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Easily bleeds with a loss of gingival stippling, with or without ulceration.
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Lesions are symptomatic or painful or even burning.
There should be:
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No vesicles, bullae, or Nikolsky sign or Wickham striae of lichenoid lesions.
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No speckled red and white lesions.
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