Clinicopathological and immunohistochemical analysis of plasma cell gingivitis- A retrospective study : Journal of Indian Society of Periodontology

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Original Article

Clinicopathological and immunohistochemical analysis of plasma cell gingivitis- A retrospective study

Gupta, Vandana; Kaur, Harpreet1; Yadav, Vikender Singh; Kala, Sunny1; Mishra, Deepika1,

Author Information
Journal of Indian Society of Periodontology: Sep–Oct 2022 - Volume 26 - Issue 5 - p 434-439
doi: 10.4103/jisp.jisp_67_21
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Abstract

INTRODUCTION

Plasma cell gingivitis (PCG) is a rare benign lesion of the gingiva with various appellations such as plasma cell gingivostomatitis, idiopathic gingivostomatitis, etc.[12] The latest 2017 World Workshop classification has included this entity under nonplaque induced gingival lesions though the previous editions have expanded its classification under conditioned gingival enlargement.[3] The predisposing factors responsible are allergic reactions to some known allergens though in the majority of the cases the cause remains unidentified.[4] Thus, PCG is classified into 3 categories; caused by allergens, neoplasms, or unknown cause.[56]

There is no particular age or sex distribution for PCG except female predominance in few.[7] Clinically it usually presents as diffuse, red, edematous enlargement of the marginal gingiva extending into attached gingiva with sharp demarcation along the mucogingival border.[8] Many a times, PCGs are associated with other mucosal lesions such as cheilitis and glossitis.[9] Microscopy shows diffuse intense infiltration of mature plasma cells in the stroma with marked epithelial changes.[41011] PCG mimics other immune-mediated mucous lesions and sometimes plasma cell dyscrasias (PCDs). Thus, in complex cases, a multidisciplinary diagnostic approach involving clinical and microscopic features along with diagnostic adjuncts such as hematology and immunohistochemistry (wherever required) is often necessary. However, the role of immunohistochemistry is not extensively studied in the diagnosis of PCG so far.

CD138 (syndecan) is a marker of plasma cells irrespective of reactive or neoplastic nature. Kappa and lambda light chain reactivity is commonly used to study the clonality of plasma cells.[9] CD56 is neural cell adhesion molecule which is expressed in 70%–80% of malignant plasma cells.[12] CD117 is hematopoietic growth factor which is observed in 33% of plasma cell myeloma (PCM) patients. However, the lack of expression of these markers in malignant plasma cell neoplasms indicates more aggressive behavior. Nevertheless, normal plasma cells are typically negative for both CD56 and CD117.[13] Ki67 is well-known cell proliferation marker related to aggressive biological behavior.[14] Mukherjee et al. studied the expression of CD44, CD34, CD43, Ki67, and CD117 in addition to kappa lambda profile in discrimination of PCG from malignancies.[15] However CD56 expression is not yet studied in PCG.

Thus, the aim of the present study was to retrospectively analyze clinico-pathological characteristics of PCG reported at a tertiary care dental hospital. We emphasize the conventional multidisciplinary approach integrating microscopic features with history, clinical and imaging details for reaching the accurate diagnosis. Further, the role of hematological investigations and immunohistochemical evaluation of CD138, CD56, CD117, Ki67, and kappa lambda in differentiating PCG from malignant neoplasms is also highlighted and the relevant literature is examined.

MATERIALS AND METHODS

After receiving institutional ethical approval and following Helsinki Declaration and their guidelines, we retrospectively reviewed 2044 biopsies received in the department of oral pathology and microbiology, from January 2018 to July 2020. The paraffin-embedded blocks of confirmed PCG cases were retrieved from the archives. All hematoxylin- and eosin-stained sections of PCG cases were analyzed. The pertinent details were retrieved from case files of patients. Periodic acid Schiff (PAS) stain was used to exclude candidiasis. To rule out overt malignancies and to confirm the polyclonal nature of plasma cells, immunohistochemistry with Ki67, CD56, CD117, CD138, Kappa, and lambda were performed for each case. These cases were re-evaluated by the pathologists and the final diagnosis of PCG was confirmed.

For the literature review, we conducted an extensive search of published English literature from 1971 to 2020 using PubMed and Google Scholar as the primary databases. The MeSH terms used were PCG, gingiva, idiopathic enlargement, maxilla, and mandible. The cases previously reported were compared with our series of PCG.

RESULTS

The study included 9 histopathological confirmed cases of PCG comprising 6 females and 3 males (M:F ratio-1:2). The age range was 14–82 years with a mean age of presentation being 45.3 years [Table 1; Figure 1].

T1-5
Table 1:
Clinical features of plasma cell gingivitis in our study
F1-5
Figure 1:
Clinical presentation of plasma cell gingivitis. (a) Extra-oral picture showing facial asymmetry. (b) Preoperative generalized gingival enlargement (frontal view). (c) Preoperative gingival enlargement (occlusal view). (d) Postoperative view after 6 months of surgical excision of enlarged gingiva (e) Orthopantomogram showing generalized bone loss

Predisposing factors remain unidentified in all except one case where there was associated implant-supported prosthesis adjacent to the lesion. Clinical differential diagnosis included idiopathic gingival enlargement, PCG, granulomatous diseases, mucocutaneous lesions, pyogenic granuloma, and rarely malignancies, namely leukemia, extramedullary plasmacytoma (EMP), and PCM. Normal hematological profile ruled out leukemia and lupus erythematosus.

Microscopy of the cases characteristically exhibited intense plasma cell infiltrates (>50%–70%) within vascular stroma with no cellular atypia and variable epithelial changes [Figure 2].

F2-5
Figure 2:
Histopathological presentation of plasma cell gingivitis. (a) Spongiotic hyperplastic epithelium overlying inflamed stroma (inset showing psoriasiform hyperplasia). (b) Epithelium showing marked acanthosis and leucocytic exocytosis (red arrow). (c) Epithelium exhibiting hyperplasia with entrapped fibrovascular cores and spongiosis. (d) Acanthosis and plasma pooling within epithelium. (e) Stroma exhibiting intense inflammatory infiltrate with interspersed engorged blood vessels. (f) High power showing predominantly plasma cells exhibiting eccentric nuclei

Epithelial characteristics

All cases were circumscribed showing epithelial covering focally with predominant areas of ulceration. All cases displayed hyperplasia, acanthosis, spongiosis while some cases showed arcading pattern (Case 2, 5, and 9) and plasma pooling (Case 6). All cases showed parakeratinization, while 4 (Case 4, 5, 7, and 8) cases showed loss of keratinization in few areas. Only 4 cases showed leukocyte exocytosis (Case 1, 2, 5, 7).

Connective tissue characteristics

There was an intense infiltration of plasma cells predominantly arranged in sheets and lobules while few cases (1, 2, and 8) showed diffuse arrangement. All the cases showed mild-to-moderate vascularity with engorged blood vessels. In addition, Case 8 showed histiocytes and multinucleated giant cells.

Histopathological differentials considered were PCG, IgG4 related disease (RD), and PCDs such as plasmacytoma and its multicentric form-PCM [Table 2]. Immunohistochemically, plasma cells in all the cases showed mixed reactivity for both Kappa and lambda (kappa lambda ratio of 1:01) confirming a polyclonal nature. These cells were negative for CD117, CD56, PAS; immunopositive for CD138 and exhibited low to negative Ki67 proliferation index (1%–4%) [Figure 3]. The published literature showed 43 reported cases of PCG from 1971 to 2020 [Supplementary Table 1].[1456791115161718192021222324252733343536373839404142434445464748]

T2-5
Table 2:
Differential diagnosis of Plasma cell gingivitis

F3-5
Figure 3:
Special staining and immunoprofile of plasma cell gingivitis. (a) Periodic acid–Schiff staining showing no fungal organisms. (b) Plasma cells exhibiting membranous and cytoplasmic cluster of differentiation 138 immunopositivity. (c) Ki67 proliferation index less approximately 1%. (d and e) Plasma cells displaying immunonegativity for CD117, CD56. (f and g) plasma cells displaying equivocal immunoreactivity for kappa and lambda light chains

DISCUSSION

In the present study, 9 cases of PCG were diagnosed in the last 3 years as compared to only 43 cases reported in the literature in the last 50 years. It can be explained by two reasons. First, it can be suggested that the low number of PCG cases is a result of under-reporting since the entity is not novel, also since only literature in English were searched and included in the manuscript, case reports in other languages were most likely overlooked. Another reason for increased frequency of PCG in our institute can be attributed to the fact that our center is an apex referral center. PCG does not always respond well to the treatment prescribed due to unidentifiable etiological factors in most situations. Hence, the patients are generally referred to higher centers for the relief of symptoms.

The analysis of the published literature revealed female predominance with male-to-female ratio of 1:1.42. The age ranged from 12 to 70 years (mean 31.6) and presentation in the pediatric age group was rare. The maxillary lesions were more common, involving the anterior gingiva in the majority of cases. The herbal toothpaste and their ingredients were recognized as risk factors in most of the cases. Clinical appearance varied from gingival enlargement (18 cases), followed by the erythematous lesion (13 cases), ulcerated swollen mass (6 cases), and gingival inflammation (6 cases).

Upon comparing the characteristic features of PCG in the published literature with our cases, similarities were observed in sex predilection where a female predominance was demonstrable, with involvement of maxillary and mandibular arch more frequently than tongue, lip, and palate.[41718] The predisposing risk factors remained unidentified in the majority of the cases in literature which is concurrent with our observations. Some reports have found herbal agents in dentifrices,[1920] Khat leaves,[21] colocasia (arbi) leaves,[1] mint,[22] fixed prosthesis, and dietary components as contributing factors. The lesions get eventually resolved by identifying the risk factor and eliminating it from the patient diet.[3] Unfortunately, in our series, the predisposing factor remains unidentified except for one case where the prosthetic component proved to be risk factor for PCG. This was consistent with the case reported by Prasanna et al.[23]

PCG clinically mimics other reactive lesions such as pyogenic granuloma, peripheral giant cell granuloma, immune-mediated mucous lesions such as cicatricial pemphigoid and discoid lupus erythematosus and histologically mimic PCDs and IgG4 RD.

Clinically the current cases showed generalized gingival enlargement involving marginal and attached gingiva with altered contour and rolled out margins that is identical to the case reported by Vishnu et al.[7] Diffuse swollen erythematous mass and gingival ulceration were observed which are consistent with previous reports.[2425] Radiographic finding of generalized horizontal bone loss was seen in a single case as mentioned in the literature.[15] Silverman has described syndromic association with the triad of PCG, glossitis, and cheilitis but no case in our series showed this association.[26] Three cases in the literature were associated with supraglottic lesions but none of our present cases showed laryngeal lesions.[27] Similarly, Tandon et al. reported a case of oral tuberculosis that mimicked PCG on incisional biopsy, however, chest radiograph and excisional biopsy confirmed it to be tubercular gingivitis.[28]

Few isolated case reports have mentioned plasma cell granuloma as a manifestation of underlying IgG4- RD (IgG4-RD).[29] IgG4-RD is a rare fibro-inflammatory systemic disease with comprehensive diagnostic criteria which is a combination of clinical, imaging, laboratory, and histopathological findings.[3031] None of our present cases could fulfill the diagnostic criteria for IgG4-RD and thus this differential was excluded.

Barbe et al. have reported a case of sickle cell anemia mimicking PCG the diagnosis of which was confirmed by altered hematological profile and electrophoresis.[16] Histopathological examination showed diffuse intense infiltrate of plasma cells in the subepithelial connective tissue with no evidence of cytological atypia. Vishnu et al. reported a case of PCG mimicking granulomatous disease.[7] Polyclonal nature of plasma cells was confirmed by kappa lambda light chain co-expression is most of the cases.

Further PCDs should be excluded before labeling a lesion as reactive PCG.[3] PCDs, are malignant neoplasms of monoclonal plasma cells exhibiting metastatic potential. Solitary plasmacytoma of bone is unicentric malignancy with origin within bone whereas EMP is predominantly seen in the head–and-neck region. PCM is systemic malignancy with multicentric origin within the bone with the same histopathology as plasmacytoma but poorer prognosis.[33233] As both reactive and neoplastic plasma cells exhibit CD138 immunopositivity, the restriction in production of one of the two (kappa and lambda) light chains is a promising way to confirm monoclonality.[3] Immunonegativity to CD117, CD56, low to negative Ki67proliferation index, and equivocal reactivity for kappa and lambda in all the present cases of PCG was in accordance with Mukherjee et al.[15] However, CD56 was evaluated for the first time in PCG. The results were in agreement with the published data which showed CD56 immunonegativity in normal plasma cells.[14]

The treatment in all cases of our study constituted gingivectomy followed by Phase I therapy and surgical excision of the lesion. Recurrence was observed in only 1 case till 2 years of follow-up (Case no. 4). However, in literature, different treatment modalities of PCG exist including nonsurgical and surgical approaches [Supplementary Table 1]. Nonsurgical treatments comprise oral and topical steroids, topical 2% fusidic acid, topical chlorpheniramine maleate, and strict elimination of recognized risk factors; surgical approach advocates gingivectomy and surgical excision.

CONCLUSION

Our study explained in detail the clinicopathological features of PCG in comparison with literature findings. Further, it can be concluded that histopathology remains the gold standard to diagnose PCG. Immunonegativity for CD56, CD117, and low Ki67 proliferation index may be used as adjunctive diagnostic characteristic (in addition to already established kappa and lambda reactivity) for differentiating it from malignant PCDs. However, instead of the small number of cases of PCG in our study, these markers should be performed on a large sample size to confirm our findings.

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Keywords:

Benign lesion; gingival overgrowth; immunohistochemistry; plasma cells

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