B-cell Follicular Lymphoid Hyperplasia (Pseudolymphoma) of the Oral Cavity: A Diagnostic Quandary

Abstract

Pseudolymphoma is a reactive process involving lymphadenopathy, polyclonal proliferation of B or T-cells, simulating oral lymphoma. With its incidence being very rare, only four cases have been reported in oral cavity with the detailed immunocytochemical examination, which can be due to this entity's unawareness, underdiagnosis or overdiagnosis. It is prerogative to perform immunocytochemical investigations to prevent overdiagnosis as lymphoma, which can be debilitating to the patient. Wherein the treatment of pseudolymphoma initially includes topical or intralesional corticosteroid, antibiotics to surgical and radiotherapy based on its etiology. Herein, we discuss B-cell follicular lymphoid hyperplasia previously diagnosed as small round cell tumor.

Introduction

Follicular lymphoid hyperplasia or pseudolymphoma (PL) is an active lymphohistiocytic proliferation due to known or unknown cause which simulate the oral lymphoma [1]. They can be categorized based on their predominant lymphocyte subtype present: T-cell, B-cell, mixed (B and T)-cell, CD-30-positive, and non-classifiable PL. Its etiology can be related to contact dermatitis, lichenoid reactions, syphilis, arthropod reactions, viral infections and certain drugs [2]. The cutaneous site being the most common site of occurrence, seldom seen in gastrointestinal sites, salivary glands, lungs, and the ocular adnexae [3]. Oral cavity presentation is rare compared to the cutaneous site and has a striking clinical resemblance to oral lymphoma. Herein, we discuss a case of B-cell follicular lymphoid hyperplasia or PL, and how a variety of ancillary procedures, such as immunohistochemistry, can aid in differentiating it from a life-threatening malignancy.

Case Report

A 65-year-old male reported to our institute with a chief complaint of large erythematous swelling in the upper left posterior region extending from Maxillary right first premolar to posterior hard palate involving the midline of the palate for past eight months. On palpation, the swelling was smooth, firm to palpate, mildly compressible and non-tender (Fig. 1). FNAC revealed chronic inflammatory cells. Based on that incisional biopsy sample taken which revealed hyperplastic stratified squamous epithelium. After six months of the initial biopsy, patient reverted with larger swelling of size 3.5 × 2.5 cm in size. Subsequently, excisional biopsy was done, microscopic examination revealed dense fibrous connective tissue stroma with intense inflammatory cell infiltrate and few scattered lymphoid follicles along with few reactive germinal centers. The germinal centers showed a mixture of mature lymphocytes, plasma cells and tingible body macrophages. Atypical small round cells with ovoid vesicular nuclei and indiscernible cytoplasm infiltrating the mucous salivary gland. These findings led us to diagnosis of small round cell tumor, with various histopathological differential diagnoses including poorly differentiated squamous cell carcinoma, lymphoma, rhabdomyosarcoma, primitive neuroectodermal tumor, amelanotic melanoma, merkel cell carcinoma. Immunohistochemical examination panel was done for definitive diagnosis. An initial panel of markers- Pan CK, CD45, S-100 and desmin was performed, amongst which Pan-CK, S-100, and desmin were negative, ruling out squamous cell carcinomas, primitive neuroectodermal tumor, amelanotic melanoma, merkel cell carcinoma and rhabdomyosarcoma respectively. Inflammatory cells showed diffuse immunopositivity for CD45 denoting the hematopoietic cellular lineage of the lesion, which led us to next set of panels comprised of CD3, CD5, CD15, CD20, CD30, CD138, CD68 and Ki-67. Out of which CD20 showed focal positivity, only in the germinal center of lymphoid follicles demonstrating B-cell origin whereas T-cell lineage was excluded with immunonegativity for CD3 and CD5. CD68 revealed scattered immunopositivity for the histiocytes, and diffuse immunopositivity of CD138 showed the presence of plasma cells. Based on the presence of B-cells, histiocytes and plasma cells and low proliferative index < 5% (Ki-67), definitive diagnosis of B-cell follicular lymphoid hyperplasia was made (Fig. 2). Patient was then referred to oral medicine department for combined topical and intralesional corticosteroid treatment and to general medicine department for alternation of his hypertensive medication. With 18-month close follow-up patient is disease free.

Fig. 1.

Photomicrograph showing intraoral view of the case

Fig. 2.

Photomicrograph under 200X A histopathological view (H&E); IHC Expression for B Pan CK; C CD 20; D CD 68; E CD 45; F CD 138

Discussion

Oral PL is a very unique dilemma faced by oral pathologists, simulating malignant lymphoma. It is a reactive polyclonal T- or B-cell lymphoproliferative process that develops in reaction to diverse known and unknown stimuli [4]. Although they appear more often in the skin, PL have also been described in other organs, such as the salivary glands, larynx, gastrointestinal tract, lung, kidney including oral cavity. Only four other cases were reported in the oral cavity along with the present case [3–5] (Table 1). All these reported cases were associated with ill-fitting prosthesis and poor oral hygiene whereas in present case, oral hygiene was poor and not associated with prosthesis. He was under angiotensin-converting enzyme inhibitor which might be the cause of the antigenic stimuli [1]. Sporadically some cases are linked to antigenic stimuli caused by certain medications (29%), tattoo reaction (26%), medicinal leeches (4%), borrelial lymphocytes (7%), SIT/Vaccines (9%), post viral infections (2%), bites/Scratches/injections (5%), HIV (2%) whereas most of the cases were idiopathic [2].

Table 1.

Published cases of oral pseudo lymphoma

References	Age/sex	Location	Size of the lesion	Prominent histopathological features	Initial diagnosis	IHC markers	Treatment	Resolution and follow up
Kabani et al. [3]	42/F	Maxillary anterior mucobuccal fold	2 × 1.5 cm	Small lymphocytes admixed with clusters of larger cells,. showing irregular nuclear contours, peripherally localized chromatin, with one or two nucleoli	Malignant lymphoma	B-cell marker = Leu14 T-cell marker = Leu4 Dendritic cell marker = OKT6	Locally excised	No recurrence 20 months post -op
Río et al. [4]	62/M	Right buccal mucosa	0.8 × 1.2 cm	Lymphohistiocytic infiltrate with histiocytic component showed nuclear features that mimicked Hodgkin's cells	Malignant lymphoma	T-cell marker = Leu22, MT1, UHCL-1 B-cell markers = L26 and Mb-2 Histiocytic marker = HAM56, Alpha-1-ACT,MAC387	Systemic Corticosteroid	Complete resolution in 4 months; and no recurrence after 4 years
Río et al. [4]	72/F	Inner aspect of lower lip	0.7 cm	Infiltrate of highly mitotic histiocytes and of the large hyperchromatic nuclei of the intraepithelial lymphocytes	Malignant lymphoma	T-cell marker = Leu22 and MT1 Histiocytic marker = HAM56,Alpha-1-ACT, MAC387	Locally excised	Spontaneous resolution within 3 weeks, no recurrence 2 years post- op
Ferrisse et al. [5]	64/M	Left buccal mucosa	NA	Foci of angiocentric and perivascular lymphoid infiltrate containing atypical cells surrounded by fibrous stroma	Malignant lymphoma	T cell marker = CD3, CD4, CD25, FOXP3 B cell marker = CD10, BCL2	Locally excised	Spontaneous resolution after 4 weeks
Present case 2023	65/M	Maxillary posterior hard palate	3.5 × 2.5 cm	Atypical small round cells with ovoid vesicular nucleus and indiscernable cytoplasm	Small round cell tumor	Hematopoitic marker = CD45 B-cell marker = CD20 Histiocytic marker = CD68 Plasma cell marker = CD138	Locally excised Along with topical steroid therapy	No recurrence after 18 months

*F female, M male, OKT-6 CD1a recombinant antibody, MT1 metallothionein, UHCL-1 Ubiquitin carboxy-terminal hydrolase L1, Alpha-1-ACT alpha-1-antichymotrypsin, MAC387 anti-macrophage marker antibody, CD cluster of differentiation, FOXP3 forkhead box P3

Clinical or histological features alone can’t confirm the diagnosis of lymphoma or PL. Only combined approach of clinical history, histological features and immunohistochemical analysis differentiates lymphocytes by their immune-phenotype (surface markers) can lead to a definitive diagnosis. Features gratifying diagnosis of lymphoma over PL are, infiltration of tumor cells into deeper stroma, monomorphic infiltrate usually comprising immature lymphoid cells of germinal center origin, changes in nuclear morphology, nuclear density and altered nuclear/cytoplasmic ratio. Usually, PL is composed of a mixture of mature inflammatory cell infiltrate comprising of follicular aggregates with typical germinal centers [6].

Oral PL is a benign lesion that does not require the severe treatment typically needed for malignant lymphoma, as stated by Saltzstein (1969). Its distinction from malignant lymphoma is more than just a matter of histological perfection [7]. In order to spare the patient from unnecessary chemotherapy and the mental suffering of an incorrect diagnosis of malignancy, it is crucial to make the diagnosis as correctly as possible.

According to previously reported cases, PL can also progress to malignant lymphoma [8]. Hence the patient has to be kept under follow up or malignant lymphoma can be misdiagnosed as PL which can lead to under treatment. Meticulous follow-up is advised at regular intervals for a minimum of one year. However, according to some authors, in the absence of curative treatment, at least five recurrence-free years following biopsy are necessary to confirm the diagnosis of PL [7].

Conclusion

We describe a case of Oral PL in order to increase physicians' and pathologists' knowledge of this condition and decrease the possibility of incorrect diagnosis and overly aggressive therapy for this benign, self-limited lesion. To diagnose PL it is required to compare clinical and histological data, evaluate the architecture and composition of the inflammatory infiltrate, and combine these results with immunohistochemistry.

Author Contributions

All the authors contributed significantly to this manuscript.

Funding

None.

Declarations

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The authors declare that they have no known conflict of interest.

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