Diffuse B-cell lymphoma in a submandibular gland: A very rare case presentation in a 23 years old

Introduction: Malignant lymphomas of a salivary gland originate from either a lymph node (nodal) or from the parenchymal tissue of a lymphoid organ (extranodal). Primary lymphomas of the salivary glands are rare in nature, accounting for 1.7–7.4% of all salivary gland tumors. Non-Hodgkin lymphomas (NHL) of salivary glands most commonly (75%) affect the parotid gland. The submandibular gland lacks presence of intraglandular lymph nodes and the incidence of extranodal lymphomas of the submandibular gland are therefore very rare. Case Report: A 23-year-old white Caucasian male reported a 3-month history of an asymptomatic lump in the right submandibular region. An ultrasound scan and a magnetic resonance imaging (MRI) demonstrated a large and well-defined hypercellular mass in the right level Ib/ submandibular region. A fine needle aspiration (FNA) and excision biopsy were performed. Fluorescence in situ hybridization (FISH) confirmed a diagnosis of a diffuse large B-cell lymphoma, non-germinal center type. The patient was treated with a 12-week chemotherapy regime (R-CHOP). A preand post-chemotherapy PET-CT (positron emission tomography-computed tomography) Farooq Hassan Afzaal1, Basil Zia Khan2, Karim Kassam3, Ashok Adams4 Affiliations: 1ACCS CT1 Anaesthetics, Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW, United Kingdom; 2Foundation Year 2 Doctor, Queen Elizabeth Hospital, King’s Lynn, Gayton Road, PE30 4ET, United Kingdom; 3Consultant Maxillo-Facial Surgeon, Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW, United Kingdom; 3Consultant Radiologist, Barts Health NHS Trust, The Royal Hospital, Whitechapel Road, London, E1 1BB, United Kingdom. Corresponding Author: Dr. Farooq Hassan Afzaal, ACCS CT1 Anaesthetics, Leicester Royal Infirmary, Infimary Square, Leicester, LE1 5WW, United Kingdom; Email: fha1993@gmail.com Received: 05 November 2020 Accepted: 24 April 2021 Published: 09 June 2021 was performed, the latter of which showed only normal physiological uptake and no recurrence or signs of distant metastasis. Conclusion: Submandibular lymphomas are a welldocumented yet rare presentation, particularly in the young adult. This case report highlights the successful diagnosis, treatment, and follow-up of an extremely rare finding in a 23-year-old patient and highlights the importance of considering a diffuse B-cell lymphoma in a patient presenting with a lump in the submandibular gland.


INTRODUCTION
Lumps of the salivary glands include a wide range of pathologies both malignant and benign. One of the malignant causes of a salivary gland lymph node includes malignant lymphomas. These are tumors originating from either a lymph node (nodal) or from the parenchymal tissue of a lymphoid organ (extranodal) [1]. Primary lymphomas of the salivary glands are rare in nature, accounting for 1.7-7.4% of all salivary gland tumors and 4.7% off all presentations of lymphomas [2,3].
Where non-Hodgkin lymphomas (NHL) occur within the salivary glands, they most commonly (75%) affect the parotid gland in either the intraglandular lymph nodes (nodal) or within the gland parenchyma (extranodal). The submandibular gland lacks presence of intraglandular lymph nodes and, therefore, the incidence of extranodal parenchymal lymphomas of the submandibular glands is very rare [4][5][6][7]. This case report highlights the first documented example of a primary diffuse B-cell lymphoma originating from the parenchymal tissue of a submandibular gland.

CASE REPORT
A 23-year-old white Caucasian male was referred to the maxillo-facial department for investigations of a painless lump in the right submandibular region. The patient reported an asymptomatic lump that had been present over a 3-month period with no prior symptoms, particularly no B-symptoms (fever, night sweats, and weight loss). The patient was otherwise fit and well with no past medical history.
The patient underwent an ultrasound scan and an MRI scan which demonstrated a large and well-defined mass in the right level Ib/submandibular region with modest heterogenous enhancement. The patient went on to have a FNA and a core biopsy, the latter of which was inconclusive. The fine needle aspiration showed morphology suggestive of a high grade non-Hodgkin lymphoma and a further biopsy was advised. The patient underwent an excision biopsy. Histopathological analysis of the biopsied specimen was suggestive of a high grade B-cell lymphoma. Fluorescence in situ hybridization (FISH) further confirmed a diagnosis of a diffuse large B-cell lymphoma, non-germinal center type.
Post-operatively, the patient underwent a PET-CT scan showing high uptake posterior to the right hemimandible and no distant metastasis. The patient was referred to the oncology team and was treated with multiple rounds of chemotherapy after which a PET-CT scan was performed showing only normal physiological uptake and no recurrence or signs of distant metastasis.

Macroscopic
The patient presented with a 3-month history of a right-sided submandibular lump (Figure 1). Following a core biopsy and a FNA the patient underwent a surgical excision that revealed a creamy, cheesy textured lymphoma like mass.

Imaging modalities
Ultrasound neck demonstrated a well-defined hypoechoic lesion in the right submandibular region ( Figure 2). This was difficult to distinguish as discrete from the submandibular gland. The patient also underwent a FNA for cytology.
An MRI of the neck revealed a large and well-defined mass in the right level 1b submandibular region. A T2-weighted image demonstrated intermediate signal while a T1-weighted post-contrast image demonstrated modest heterogenous enhancement ( Figure 3).
Axial diffusion-weighted imaging with a b1000 image and apparent diffusion coefficient (ADC) map demonstrated diffusion restriction compatible with a hypercellular lesion ( Figure 4). This finding on axial diffusion-weighted scan was highly suggestive of a malignant cause.

Cytology
Four air-dried samples were processed for cytology from the FNA revealing a population of lymphoid cells with a marked increase in nuclear to cytoplasmic ratio, irregular nuclear outlines, and nuclear hyperchromasia. Scattered mitotic figures were also seen. No germinal center fragments were noted and only occasional small lymphocytes were seen scattered in the background ( Figure 5). The findings were suggestive of a high grade non-Hodgkin lymphoma.
Microscopically, most of the salivary glands were within normal limits. An enlarged lymph node which was partially replaced by a vaguely nodular infiltrate of centroblasts with scattered tingible macrophages was seen. No necrosis was observed. Part of the same lymph node showed normal germinal centers. Several smaller lymph nodes showed reactive changes only.
Immunostains showed that the large cells were B-lymphocytes: CD20+, BCL6+, and bc12+ (weak) with high proliferation rate, MIB1 60-70%. There was an underlying moth eaten follicular dendritic cells (FDC) meshwork on CD21. Staining for CD30, CD5, and EBER was negative. The features were those of high grade B-cell lymphoma, likely diffuse large B-cell lymphoma (DLBCL), non-germinal center type. Some features suggest that this might have arisen from an underlying low grade lymphoma, either follicular lymphoma or marginal zone lymphoma. Fluorescence in situ hybridization (FISH) was negative for c-myc and bc12 translocation and positive for BCL6 translocation (Figure 6). This was entirely in keeping with diffuse a large B-cell lymphoma, non-germinal center type.

Follow-up
Post-operatively, the histology of the surgically excised neck lump confirmed a DLBCL. The patient was referred to the oncology team for further management where a 12-week chemotherapy regime (R-CHOP) was arranged. The therapy consisted of Rituximab, Cyclophosphamide, Doxorubicin Hydrochloride, Vincristine, and Prednisolone. To assess for response to chemotherapy, the patient underwent a PET-CT scan showing only normal physiological uptake and no area of concern at the site of the excision and no concerns of recurrence or distant metastasis (Figures 7 and 8).

DISCUSSION
Common differentials for a neck lump arising from the submandibular gland are divided into two categories, non-neoplastic, and neoplastic. Non-neoplastic differentials include sialadenitis and sialolithiasis. Neoplastic differentials include pleomorphic adenoma, mucoepidermoid carcinoma, adenocarcinoma, and lymphoma. Often the history of presentation and examination of the neck lump can help clinicians determine the nature of the lump (infective, obstructive, or malignant). Sialadenitis and sialolithiasis commonly present with a shorter history of a warm, erythematous tender submandibular neck lump accompanied with malaise and pyrexia. In the case of a hematological malignancy presenting as a neck lump, patients commonly present with B-symptoms suggestive of a neoplastic cause. B-symptoms commonly include unexplained pyrexia, night sweats, and unexplained weight loss.
In this particular case, the patient presented with a three month history of a non-tender neck lump in the absence of infective symptoms, raising suspicion for a neoplastic lump. Absence of B-symptoms in this patient's presentation would suggest a non-hematological malignancy.
As per local and national guidance, the least invasive form of imaging was arranged under a 2-week wait and the patient underwent an ultrasound scan with a FNA and core biopsy. An MRI scan was also performed and the hypercellular findings on the diffusion weighted images were highly suggestive of a malignant cause. This highlights the importance of MRI scanning in the workup of head and neck masses.
Although the results of the core biopsy were inconclusive, the high level of suspicion for a malignant cause led to an early excision rather than a repeat biopsy. The cytology from FNA samples was highly suggestive of lymphoma which was later confirmed on histology of the surgically excised mass. An early referral was made to an oncological department where a chemotherapy regime had been advised for the patient. After 12 weeks (four 3-week cycles) of chemotherapy, a post-treatment PET-CT scan was performed. This showed a normal physiological uptake and no evidence of recurrence at the site of the excision and of distant metastasis.
This case demonstrates a rare occurrence of DLBCL in a submandibular gland and the first of its kind to be documented in a young and otherwise healthy adult of only 23 years of age. It highlights the importance of considering lymphoma in the set of differentials when working up a neck lump in an otherwise young and healthy adult. Current literature suggests that lymphomas are more commonly seen in parotid glands as compared to submandibular glands [8]. However, this case suggests that lymphoma within the submandibular gland is a possibility despite the lack of intraglandular lymph nodes. Furthermore, the diagnosis of DLBCL highlighted the need for further work up to assess for local or distant spread. As mentioned earlier, post-operative PET-CT in this case did not show any signs of distant metastasis and patient was classified as having DLBCL stage 1a.
Diffuse large B-cell lymphoma is one of the more aggressive forms of NHL and makes up 40% of all NHL cases in adults [9]. It is more common in men compared to females [9]. Oncological management is based around chemotherapy, immunotherapy, and radiotherapy. Early stage DLBCL is typically treated with three to four cycles (each cycles lasts three weeks) of chemoimmunotherapy. In our case a surgical excision of the tumor was undertaken followed by four 3-week cycles of R-CHOP chemotherapy leading to complete metabolic remission. The case also highlights the importance of a multi-disciplinary approach to a very rare presentation.

CONCLUSION
Lymphomas originating in the submandibular salivary glands are a rare but well-documented occurrence. This case report emphasizes the importance of including lymphoma in the differentials of young patients being investigated for a suspicious neck lump. This case highlights the successful diagnosis, treatment, and follow-up of an extremely rare finding. *********

Author Contributions
Farooq Hassan Afzaal -Conception of the work, Design of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Basil Zia Khan -Conception of the work, Design of the work, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Karim Kassam -Conception of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Ashok Adams -Acquisition of data, Analysis of data, Interpretation of data, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

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Consent Statement
Written informed consent was obtained from the patient for publication of this article.