Plasma cell mucositis with gingival enlargement and severe periodontitis.

Plasma cell mucositis (PCM) is a very rare, chronic, multifocal, idiopathic, non-neoplastic plasma cell proliferative disorder of the upper aerodigestive tract. The classic clinical presentation is an intensely erythematous mucosa with surface changes described variously as papillomatous, cobblestone, nodular or velvety. It is a very rare condition <50 cases reported in literature. A 72-year-old male patient complained of sore throat, stomatodynia, dysphagia, multiple oral ulcers, enlarged swollen bleeding gums and mobile teeth. There was chronic inflammatory enlargement of the gingiva and palate with severe periodontitis. Histopathological examination revealed a hyperplastic epithelium with a dense infiltrate of mature polyclonal plasma cells in the superficial layer of the lamina propria. PCM is a diagnosis of exclusion, to be differentiated from other infective, reactive, autoimmune, allergic and neoplastic disorders with plasma cell infiltrates. Management with surgical and immunosuppressive therapy is mostly ineffective with short remissions and frequent relapses.

INTRODUCTION

Plasma cells are normally found in bone marrow and the intestinal tract. Plasma cell infiltrates in connective tissue can be seen in malignant, auto immune, reactive, infectious and idiopathic conditions. A non-neoplastic proliferative infiltrate of plasma cells in connective tissue has been reported in various anatomical sites. In 1952, Zoon first described plasma cell infiltrates in the glans penis, which he called as balanitis plasma cellularis. This condition was reported by others as well and came to be known as Zoon's balanitis.[1] Other anatomical sites with such plasma cell infiltrates reported in literature are the vulva, gingiva, buccal mucosa, palate, nasal aperture, lips, tongue, epiglottis, larynx, pharynx, lower respiratory tract, conjunctivae, skin and other orificial mucosa.[2345] Plasma cell mucositis (PCM) is the term used for disease involving the mucosa of the oral cavity and upper aerodigestive tract. It was previously reported as plasma cell orificial mucositis, idiopathic plasmacytosis, mucous membrane plasmacytosis of the upper aerodigestive tract, oral papillary plasmacytosis, idiopathic plasmacytosis of the oral and supraglottic area etc.[256]

PCM is a chronic, multifocal, idiopathic, non-neoplastic plasma cell proliferative disorder of the upper aerodigestive tract. It is a very rare condition with less than 50 cases reported in literature.[7] The clinical and histological features of PCM resemble many common benign and neoplastic conditions of the oral cavity and hence it is a diagnosis of exclusion requiring extensive investigations and multidisciplinary evaluation. A rare case of PCM in an elderly male patient causing chronic oral stomatitis, gingival enlargement, severe periodontitis, stomatodynia and dysphagia is presented. The diagnostic and management challenges encountered are also described.

CASE REPORT

The present case report is about a 72-year-old male patient who reported with oral discomfort and difficulty in swallowing since past 5 months. He gave a history of soreness of the oral mucosa with burning sensation on eating spicy food since past 9 years, but his symptoms had exacerbated in the past 5 months. He now complained of sore throat and difficulty in swallowing solids since past few months forcing him to a semisolid and liquid bland diet. He complained of multiple ulcers in the mouth and enlarged swollen bleeding gums, which had not resolved with symptomatic treatment given by his physician (topical lignocaine gel and chlorhexidine mouthwash). He informed that several of his teeth had progressively become mobile and had spontaneously exfoliated in the past 2 years. The partial denture that he had been using had become tight and was painful on insertion in the oral cavity. He found it difficult to eat or speak clearly without his denture.

He had been diagnosed with benign prostrate hyperplasia but was otherwise well and did not have any history of constitutional symptoms like fever, loss of appetite/weight, fatigue and arthralgia. He did not have any habits of smoking, tobacco and alcohol. There was no history of allergies or family history of similar condition. There was no history of skin, ocular or genital lesions. He did not have any systemic illnesses such as diabetes, hypertension, rheumatoid arthritis and was not taking any regular systemic medications.

On examination, there were erosive areas on the buccal mucosa, palate and tongue. There was no evidence of any vesicles, bullae or scarring and Nikolskys sign was negative. There was generalized inflammatory enlargement of the gingiva including the palate, extending into the pharynx. The gingiva, palatal and oropharyngeal mucosa was fiercely erythematous, edematous, with a cobble-stone like velvety shiny irregular surface which bled on palpation. According to the World Health Organization (WHO) toxicity criteria for oral mucositis the oral condition of the patient was indicative of grade 3 of severe mucositis (ulcers, extensive erythema, patient cannot swallow solid diet). The maxillary and mandibular arches were edentulous posteriorly. The remaining anterior teeth were mobile with pathological migration, gingival recession and purulent discharge from the pockets [Figures 1 and 2]. The submandibular and submental lymph nodes were palpable, mobile and tender on palpation.

Figure 1

Erythematous, edematous, inflamed gingival and palatal mucosa extending posteriorly into soft palate and oropharynx (black arrow)

Figure 2

Severe periodontitis with erythematous, edematous and inflamed gingiva in mandibular anterior teeth

Based on the clinical findings, this condition could be due to local factors or it could be an oral manifestation of a systemic condition. The differential diagnosis considered is shown in Table 1.

Table 1

Differential diagnosis

Further investigations were carried out after obtaining informed written consent from the patient. The results of the various investigations carried out are shown in Table 2.

Table 2

Results of various investigations

Based on clinical, radiological [Figure 3], histopathological findings [Figures 4–7] and results of various investigations a diagnosis of PCM was made.

Figure 3

Orthopantomogram shows generalized periodontal bone loss and missing posterior teeth

Figure 4

Infiltration of predominantly plasma cells in lamina propria (H and E, ×10)

Figure 7

Plasma cells showing lambda light chain restriction (×40)

The patient was prescribed topical corticosteroids (tablet betamethasone 1 mg as a mouthwash and gargles 4 times daily, Triamcinolone acetonide gel 0.1% for topical application 4 times daily). Symptomatic treatment for oral burning sensation (lidocaine gel) was prescribed for local application before meals to prevent discomfort while eating. The patient was followed-up weekly. At 2 months follow-up, there was only mild improvement in the oral burning sensation while the gingival bleeding had stopped. There was however no improvement in the erythematous, edematous appearance of the palatal and gingival lesions. The erosions in the buccal mucosa and tongue also persisted. The anterior teeth became progressively mobile and were extracted. The patient was then prescribed systemic corticosteroids (tablet prednisolone 60 mg once daily) along with topical application of corticosteroids and antifungal mouth paint. The patient was also prescribed proton pump inhibitors and calcium supplements prophylactically to prevent side-effects of long term corticosteroid therapy. The patient was followed weekly and at 2 months follow-up, the erosions in the buccal mucosa and tongue had resolved. There was significant improvement in the clinical appearance of the gingival, palatal and pharyngeal lesions on oral and endoscopic examination [Figures 8 and 9]. The patient reported improvement in swallowing food (able to swallow solids) and oral burning sensation. The oral condition was indicative of grade 1 according to the WHO toxicity criteria for oral mucositis (soreness ± erythema). The patient was also able to resume the use of complete dentures. The systemic steroid was gradually tapered off over the next 6 weeks. There was a relapse of the lesions in the following month. Attempts at surgical excision of the hyperplastic lesions in the gingiva and palate also resulted in recurrence. Topical application of tacrolimus (0.1%) or 2% fusidic acid also did not yield any results. The patient was restarted on systemic steroids and is now maintained on a dose of 10 mg of prednisolone and topical antifungals for the past 3 months. Attempts at further reduction of prednisolone results in relapse and increase in oral symptoms. Regular monitoring for side-effects of long term steroid therapy is carried out.

Figure 8

Decrease in erythema and edema of palatal mucosa and gingiva, post treatment with systemic steroids

Figure 9

Resolution of erythema and edema of gingival and alveolar mucosa in the mandibular arch, post treatment with systemic steroids

Plasma cells showing eccentrically placed cart - wheel nuclei with occasional halo. (H and E, ×400) (black arrow showing typical plasma cell)

Plasma cells showing kappa light chain restriction (×40)

DISCUSSION

PCM is usually more common in males in the elderly age group, the average age being 56.6 years. The classic presentation of PCM is an intensely erythematous mucosa with surface changes described variously as well demarcated plaques, warty, lobulated, papillomatous, cobblestone, nodular or velvety. Common symptoms are oral pain, dyspnea, dysphnea, sore throat, dry cough, persistent hoarseness, gingivitis and oral burning sensation. When the lesions involve the lower respiratory tract then symptoms of stridor, dyspnea and sleep apnea may also be evident. The condition is chronic and majority of the cases are associated with autoimmune or immunologically mediated disease such as seronegative rheumatoid arthritis, diabetes mellitus, psoriasis, polymyositis and Raynaud’ phenomenon. Most laboratory investigations are negative except for slight elevation of erythrocyte sedimentation rate and gamma globulin. There is no history of frequent use of common oral allergens or evidence of allergy on patch testing.[2345]

Histological features reported are epithelial hyperplasia with acanthosis and spongiosis. However some have reported epithelial atrophy and ulceration. The reteridges are narrow and elongated, whereas suprapapillary thinning and dyskeratosis may also be seen. The epithelium has also been reported as psoriasiform or showing pseudoepitheliomatous hyperplasia. A dense subepithelial plasmacytic infiltration is seen in the superficial lamina propria. The plasma cells are mature showing no atypia or prominent nucleoli. There may be few polymorphonuclear leucocytes and lymphocytes with exocytosis and microabscess formation as a result of ulceration and secondary non-specific inflammation. Occasional Russell bodies may be seen. Immunoperoxidase staining shows a polyclonal plasma cell infiltration with mixed population of kappa and lambda light chains and various heavy chains. Gene rearrangement studies may be required if results of immunohistochemical studies are in conclusive.[24] In this case histopathology revealed parakeratinized hyperplastic epithelium with a dense infiltrate of chronic inflammatory cells consisting predominantly of mature plasma cells in the submucosa. Morphologically the cells showed eccentrically placed cart-wheel nuclei with occasional halo which is typical of plasma cells. There was no evidence of carcinoma, amyloid deposits or granulomas. Immunofluorescent studies were negative for deposition of immunoglobulins or fibrinogen. Immunohistochemistry revealed a mixed population of kappa and lambda cells [Figures 4–7]. Gene rearrangement studies were not carried out due to lack of facilities, but the immumohistochemistry was conclusive of polyclonality of plasma cells.

Plasma cell infiltrates in connective tissue can be seen in malignant, auto immune, reactive, infectious and idiopathic conditions Reactive lesions like plasma cell gingivitis (PCG), neoplastic lesions like extramedullary plasmacytoma (EMP) and infectious lesions like Syphillis should be considered. Others like plasma cell granuloma, plasmacanthoma, plasmacytoid lymphoma, rhinoscleroma can also be considered although clinical presentation of these conditions are quite different from PCM.[24]

The lesions of PCG are limited to the oral cavity and only one case of laryngeal involvement has been reported. PCG has been associated with the use of highly flavored chewing gum, candies, foods or dentifrices and is considered to be a hypersensitivity reaction which resolves once the offending agent is removed. The history spans a period of weeks or months unlike PCM, which is a long standing condition of several years. PCM is considered to be idiopathic with no association with common oral allergens and recalcitrant to treatment.[289]

Plasma cell tumors are neoplastic proliferation of B cells that may appear in disseminated form (multiple myeloma), or solitary bone lesions (solitary bone plasmacytoma) or in soft tissues (EMP). EMP comprises about 3% of all plasma cell tumors. They are more commonly seen in the 5th-6th decades of life and more commonly in men. 80-90% of EMP arises from the mucosa associated lymphoid tissue in the aerodigestive tract like the nasal cavity, nasopharynx, paranasal sinuses and tonsils. They can also be seen in the oral cavity as painful tumor masses involving the alveolus causing discomfort and loosening of teeth. They are usually unifocal and show a monoclonal proliferation of plasma cells unlike PCM. Monoclonal proliferation of plasma cells has been reported in a single case of PCM in which the presence of benign clinical features were helpful in excluding EMP.[2]

It is very important to investigate the benign/neoplastic nature of the plasma cell infiltrate, as the management and prognosis of plasma cell neoplasms are very different from benign conditions. Gene rearrangement studies can be done when results of immunohistochemistry are inconclusive.

Lesions of secondary syphilis can also show plasma cell infiltrates but other histological features like unusual epithelial hyperplasia, endarteritis, neuritis, presence of spirochaetes and positive serological tests for syphilis can help in differentiating it from PCM.

In this case investigations done excluded all the conditions considered in the differential diagnosis. The results indicated an idiopathic condition like PCM with plasma cell infiltrates in the submucosa.

Management of PCM is mostly symptomatic and various treatment modalities have been mostly unsuccessful. Corticosteroids (topical, intralesional, systemic) have been tried with some success. Other topical immunosupressants like tacrolimus and cyclosporine, topical and systemic antifungals such as nystatin and griseofulvin, topical 2% fusidic acid and oral antibiotics are other therapeutic options used in PCM. Use of systemic chemotherapy (cyclophosphamide, vincristine and prednisolone) and low dose radiotherapy has also been reported in severe disease. Debulking procedures like surgical excision, or excision by CO2 lasers, electrocoagulation and cryotherapy have provided temporary relief followed by recurrence.[2345]

PCM is considered to be a benign condition and there has been no report of progression to plasma cell neoplasm. Malignant transformation to squamous cell carcinoma recently reported in PCM could be due to immunosuppressive therapy and chronic inflammation. Long-term use of immunosuppressives should be used with caution in PCM.[5] PCM is more common in the elderly age group where other co-existing systemic conditions like diabetes, hypertension, hyperacidity and osteoporosis can further complicate the management with long term systemic corticosteroids. Progression of condition has been reported in few cases leading to subglottic strictures, stenosis and respiratory obstruction requiring emergency intubation and tracheostomy.[4]

Interleukin-6 (IL-6) plays a critical role in B cell differentiation to plasma cells and abnormal production of IL-6 has been suggested to be involved in polyclonal plasmacytosis and plasma cell neoplasms. Agents that interfere with IL-6 activity can play a role in the treatment of proliferative plasma cell lesions like PCM.[10]

The exact etiology of PCM is not known, but it may be result of hypersensitivity reaction to other unidentified environmental antigens. Long-term follow-up and new treatment strategies are therefore required.