Isolated Mental Nerve Neuropathy as the First Clinical Sign of Nodal Marginal Zone Lymphoma: A Diagnostic Challenge

Introduction

Numb chin syndrome (NCS) is a rare neuropathic condition and a clinical manifestation of mental nerve neuropathy and is characterized by numbness, pain, or altered sensation in the distribution of the mental nerve.

Diseases or injuries affecting mandibular nerves have various causes. Dental causes of sensory disturbances include inflammatory processes, such as severe apical periodontitis or odontogenic abscesses, as well as traumatic events related to dental treatment or tooth extraction [1–3]. Nerve injury related to local anesthetic administration can also occur [4].

Non-dental causes include mandibular fractures, inflammatory conditions such as osteomyelitis, and nerve compression or infiltration due to tumor growth [5–7]. Typically, clinical examination allows differentiation between dental and non-dental origins. Imaging techniques such as orthopantomogram, computed tomography (CT), or magnetic resonance imaging (MRI) are required for differential diagnosis.

Although uncommon, neoplastic infiltration of the mental nerve is an important differential diagnosis in patients with prolonged pain or sensory disturbances and has been associated with systemic malignancies, particularly lymphoproliferative disorders and metastatic disease. Malignancy-associated NCS has been reported to carry adverse prognostic implications, as it can precede the diagnosis of advanced or disseminated disease [8].

Marginal zone lymphomas are indolent B-cell non-Hodgkin lymphomas that account for approximately 5% to 10% of all cases [9]. Nodal marginal zone lymphoma (NMZL) is a distinct and relatively rare subtype, representing about 1% to 2% of all non-Hodgkin lymphomas [9]. According to the current lymphoma classification, NMZL is defined as a primary nodal lymphoma that lacks evidence of extranodal or splenic involvement at diagnosis [10]. Clinically, NMZL typically presents with painless lymphadenopathy and an indolent course, while extranodal manifestations and neurological symptoms are uncommon.

We report a rare presentation of a marginal zone lymphoma manifesting solely as NCS. This case highlights the diagnostic relevance of subtle neuropathic symptoms and underscores the importance of considering underlying hematologic malignancies in patients with unexplained or persistent sensory disturbances of the mandibular region.

Case Report

A 57-year-old female patient presented to the Department of Oral and Maxillofacial Surgery of Ludwig Maximilians University Munich. She reported persistent pain in the innervation area of the left mental nerve, which had been present for approximately 2 years. Symptoms were initially characterized by intermittent pain and hypesthesia, with a pain intensity of 2 to 3 out of 10 on the visual analog scale.

Her medical history revealed a previous consultation 2 years before for hypesthesia in the distribution of the left mental nerve. A contrast-enhanced MRI of the facial skeleton at that time demonstrated mild bone marrow edema of the mandible in the region of the left mental foramen, which was interpreted as an inflammatory thickening with adjacent periostitis according to the radiology report (Figure 1). Additional inflammatory changes were noted along the course of the left mental nerve; however, the presence of a mass remained uncertain. Routine clinical follow-up was scheduled.

Over the following months, symptoms persisted and gradually progressed. Approximately 18 months after symptom onset, the patient consulted an oral and maxillofacial surgeon in private practice near her hometown. A limited incisional biopsy obtained at that time revealed a neuroma in the region of the left mental nerve. However, given the small perineural sample size, this finding was considered likely to reflect non-representative tissue sampling, as infiltrative or nodal lymphomas can be missed in limited biopsies of the mental nerve region. An MRI subsequently performed by the referring surgeon demonstrated a suspicious space-occupying lesion involving the region of the left mental nerve and the left submandibular gland, along with bilateral lymphadenopathy (Figure 2). Consequently, the patient was referred back to our department for further evaluation and management.

On clinical examination, multiple palpable space-occupying lesions were detected in the region of the left mental foramen and left submandibular area. Ultrasonographic evaluation revealed a homogeneous space-occupying lesion measuring 22×20 mm within the left submandibular gland and another homogeneous lesion measuring 15×19 mm in the region of the left mental foramen. Additionally, anesthesia was noted in the sensory distribution of the left mental nerve.

The patient’s medical history was otherwise unremarkable except for arterial hypertension, which was well controlled under medical therapy. There was no known family history of hematologic or oncologic diseases. The patient did not smoke, reported no relevant alcohol consumption, and denied illicit drug use. No occupational exposure to known carcinogens, radiation, or toxic substances was reported.

Given the progressive symptoms, inconclusive prior imaging and biopsy results, and ongoing diagnostic uncertainty, surgical exploration was undertaken primarily for definitive histopathological diagnosis and local symptom control. Surgical exploration and resection were performed under general anesthesia (Figure 3). The procedure included lateralization of the left inferior alveolar nerve to allow safe access to the lesion, targeted perilesional soft-tissue excision in the region of the mental foramen with partial osteotomy, and removal of the lymph nodes in level IB, including the left submandibular gland.

Histopathology demonstrated NMZL involving a level I lymph node. Immunohistochemistry showed neoplastic B cells expressing CD20 with co-expression of BCL2. The tumor cells were negative for cyclin D1, CD5, CD10, and BCL6. The Ki-67 proliferation index was approximately 10% to 15%. In addition, vascular and nerve-containing adipose connective tissue showed infiltrates of the same lymphoid neoplasm at the resection margins. The diagnostic course is summarized in Table 1.

Based on the postoperative interdisciplinary tumor board discussion, further imaging was advised for staging, followed by referral to the Department of Hematology and Oncology for further management.

Staging with contrast-enhanced CT of the neck, thorax, and abdomen demonstrated nodal lymphoma manifestations in the cervical, thoracic, abdominal, and inguinal regions, as well as marked bone marrow densifications, without evidence of extranodal involvement. Subsequently, the patient developed a significant increase in swelling of the left mandibular region, accompanied by severe pain (visual analog scale score of 8–9/10), most likely due to lymphoma-related nerve compression. This occurred despite analgesic therapy with oxycodone 10 mg twice daily.

In the hematologic tumor board, local radiotherapy of the mandibular manifestation for localized symptom control and 4 cycles of rituximab monotherapy were recommended. Rituximab monotherapy was chosen based on the indolent disease biology and disseminated nodal involvement without extranodal organ compromise, in accordance with established treatment strategies for symptomatic advanced NMZL [9]. After the first dose of rituximab, the patient reported a noticeable improvement in pain symptoms.

Subsequently, radiotherapy was administered using a volumetric modulated arc therapy plan with daily image-guided irradiation and a total dose of 4.0 Gy to the affected mandibular region, resulting in further clinical improvement.

Discussion

NCS causes numbness, pain, or altered sensation in the mental nerve distribution, typically affecting the chin and medial lower lip, often unilaterally. While NCS can result from a variety of dental or non-dental causes, neoplastic etiologies – either from local tumor invasion or systemic malignancy – are frequently underrecognized, which may lead to delayed diagnosis and treatment. NCS can be also caused by malignancies with bone infiltration. Metastatic involvement of the jaws is uncommon, accounting for approximately 1% of all oral malignancies, with the mandible being more frequently affected than the maxilla [11]. Clinically, patients often present with vague odontogenic pain, swelling, or NCS as an early manifestation of metastatic spread [12]. Radiologic findings are typically nonspecific and can mimic inflammatory or cystic lesions, contributing to diagnostic delay. Several case series have highlighted that NCS can precede the detection of systemic metastases or even be the first clinical sign of recurrent breast cancer [13].

Malignancy-associated NCS can result from nerve compression by adjacent tumor masses, perineural infiltration along the nerve sheath, or lymphatic spread with regional nodal disease near the mental foramen [8]. These mechanisms can overlap and explain neuropathic symptoms even when early imaging lacks a discrete destructive mandibular lesion.

NCS can also occur as a manifestation of medication-related osteonecrosis of the jaw. The pathogenesis involves local bone necrosis and inflammatory compression or irritation of the inferior alveolar nerve, most commonly in patients receiving bisphosphonates or denosumab [14]. Several reports have described mental nerve neuropathy as an early or prodromal sign of developing medication-related osteonecrosis of the jaw, preceding radiographically visible bone exposure [15]. In the present case, the patient’s medical history revealed no prior use of antiresorptive medication.

Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma and includes 3 variants: nodal, splenic, and extranodal MZL [16]. The nodal form, a rare subtype, typically exhibits indolent behavior but is often disseminated at diagnosis, with bone marrow involvement occurring in approximately 30%to 40% of cases. Lymphadenopathy of the head and neck region is frequently observed, and nearly half of patients present with stage III or IV disease [17]. NMZL typically presents with nonspecific, heterogeneous features, reflecting diagnostic challenges and variable exclusion of other entities [17]. Asymptomatic cases may be managed through observation, while localized disease is treated with radiotherapy and symptomatic advanced-stage disease with chemoimmunotherapy, most commonly rituximab-based regimens [9]. Five-year survival rates vary from 64% to 89% [17].

In previously reported malignant NCS cases, patients frequently present with rapidly progressive sensory loss and are often diagnosed after detection of widespread systemic disease or obvious osseous destruction on imaging. In the cohort described by Lossos et al, NCS occurred in patients with known malignancy or was followed by the diagnosis of advanced cancer, with many cases attributable to metastatic disease or lymphoproliferative neoplasms [8]. In contrast, our patient experienced a long symptom duration of approximately 2 years with initially inconclusive imaging findings. This prolonged, indolent course contrasts with many previously reported cases of malignancy-associated NCS, which often present with rapidly progressive neuropathy in the setting of advanced systemic disease. In such acute presentations, the underlying malignancy is usually detected promptly, whereas in slowly evolving cases with subtle imaging findings, as in our patient, diagnostic delay is more likely.

A key difference between our case and many published reports is the absence of early, definitive radiologic signs of a tumor mass or destructive mandibular lesion. Early MRI demonstrated only mild bone marrow edema near the mental foramen and inflammatory changes along the mental nerve course, which were interpreted as benign inflammatory findings. Early malignant involvement of the mental or inferior alveolar nerve may be difficult to detect on MRI, as early perineural spread and subtle mandibular marrow involvement can appear nonspecific and mimic inflammatory change, thereby obscuring an underlying malignant process [18]. However, the uniqueness of our case lies in the fact that NMZL was ultimately confirmed in lymphatic tissue of the submandibular region with additional infiltrates in nerve-containing soft tissue, indicating that neuropathy can result from perineural involvement and local compression even without striking early bone destruction.

In unexplained persistent unilateral NCS, 18F-FDG PET-CT may help detect occult systemic disease, guide selection of the most metabolically active biopsy site, and support staging, although FDG uptake can be variable in indolent lymphomas [19].

Furthermore, unlike cases in which NCS is associated with aggressive hematologic malignancies and systemic deterioration within weeks [20], the indolent biology of NMZL likely explains the protracted course in our patient. Malignant NCS is not restricted to rapidly progressive cancers and can be the presenting symptom of indolent lymphomas.

Another instructive aspect is the initial biopsy result indicating a neuroma. The initial biopsy was limited and potentially non-representative, reflecting a sampling limitation rather than a diagnostic error. Compared with cases in the literature, our case illustrates that limited tissue sampling can obscure an underlying lymphoma, particularly when the lesion involves small perineural or nodal infiltrates. This emphasizes the need for careful clinicopathologic correlation and consideration of repeat or deeper sampling when symptoms persist despite inconclusive histopathology.

The principal contribution of this case lies in demonstrating that indolent nodal lymphomas can initially present with isolated mental nerve neuropathy long before systemic disease becomes radiologically apparent. In this context, symptom persistence rather than severity should prompt diagnostic escalation. Our findings suggest that even mild but progressive unilateral neuropathy warrants reconsideration of the initial diagnosis when imaging and histology remain inconclusive.

Finally, our patient developed severe pain and swelling later in the course, most likely due to lymphoma-related nerve compression, and responded quickly after initiation of rituximab and radiotherapy. This clinical response supports the malignant etiology of the neuropathic symptoms and underlines the value of timely hematologic referral and systemic staging once malignancy is suspected.

It is important to emphasize that unilateral mental nerve neuropathy is most commonly caused by benign dental, inflammatory, or traumatic conditions and does not in itself indicate malignancy. Diagnostic escalation should therefore be guided by persistence, progression, or discordance between clinical symptoms and radiological findings, rather than by neuropathy alone.

This case highlights a diagnostically challenging presentation of NMZL manifesting as isolated NCS with initially inconclusive imaging and biopsy findings, underscoring the importance of longitudinal clinical assessment and reassessment in persistent neuropathic symptoms.

This report has several limitations. As a single-case observation, the findings cannot be generalized and are intended primarily to illustrate diagnostic challenges rather than establish causal relationships. Furthermore, 18F-FDG PET-CT was not performed at initial presentation and therefore could not be assessed for its potential role in earlier detection. No extended molecular or immune profiling was available to further characterize the biological behavior of the lymphoma. Finally, the precise reasons why early MRI findings remained nondiagnostic cannot be fully determined, as subtle perineural or marrow infiltration may have been below the detection threshold at that stage.

Conclusions

A comprehensive evaluation is necessary for persistent unilateral inferior alveolar or mental nerve neuropathy to rule out the possibility of occult malignancy and to establish a structured diagnostic process. Rather than providing reassurance based on initially inconclusive findings, ongoing symptoms should prompt systemic re-evaluation, repeat imaging, and reconsideration of tissue sampling. This approach may facilitate earlier diagnosis and prevent avoidable diagnostic delay, particularly in indolent lymphoid malignancies.