Numb chin syndrome as the initial presentation of posttransplant lymphoproliferative disorder

Numb chin syndrome is a sensory neuropathy caused by compromise of the mental nerve, the posterior branch of the inferior alveolar nerve, which leads to numbness or tingling in its respective distribution. There is no loss of motor function, as the inferior alveolar nerve contains no motor fibers. While associated with certain benign etiologies (1–3), the condition is increasingly reported as a manifestation of malignancy, including prostate adenocarcinoma (4, 5), lymphoma and leukemia (6–8), multiple myeloma (9), and breast cancer (10). While many of these malignancies are associated with other historical or physical signs or symptoms, numb chin often presents as the initial symptom (11–15), and awareness of this physical finding should raise suspicion for an underlying malignancy and may even contribute to earlier detection.

CASE PRESENTATION

A 67-year-old white man initially presented to the emergency department at Baylor University Medical Center at Dallas with a 3-day history of new-onset bitemporal headache and a 1-day history of right lower lip swelling and numbness of the mandibular area. A 12-point review of systems was otherwise unremarkable. Right lower lip erythema and anesthesia were confirmed on examination, although other sensory or motor deficits were not found. The patient's gait was normal, cranial nerves were intact, and neck movements were normal. Notably, hepatosplenomegaly and lymphadenopathy were not evident on physical examination. Due to our patient's initial presentation with neurologic symptoms in the context of immunosuppression, he was admitted to rule out an infectious etiology and to undergo a diagnostic workup.

Our patient's past medical history included gastroesophageal reflux disease treated with Nissen fundoplication, hypothyroidism, systemic hypertension, and idiopathic pulmonary fibrosis diagnosed by video-assisted thoracotomy with lung biopsy at age 63, for which he underwent bilateral sequential lung transplantation at age 66 (in October 2011). Postoperatively, he developed bilateral pulmonary infiltrates and was treated with broad-spectrum antibiotics. Fiberoptic bronchoscopy revealed acute lung injury. He was treated with high-dose corticosteroids for presumed acute transplant rejection but subsequently experienced worsening pulmonary infiltrates, which required repeat workup. A repeat fiberoptic bronchoscopy with biopsy confirmed acute lung injury with organization and acute rejection. Another course of corticosteroids appeared to result in improvement. He was then treated with a 10-day course of antithymocyte globulin (Atgam) for presumed chronic rejection and also had a tracheostomy because of prolonged respiratory failure. After this intervention, he was gradually weaned off the ventilator, the tracheostomy was removed, and he was eventually discharged home with no pulmonary complaints. In addition to receiving treatment for this episode of acute rejection, our patient was kept on a baseline immunosuppressive regimen of tacrolimus and azathioprine.

A sister had died at age 75 from complications of chronic obstructive pulmonary disease, and the patient was a former 20 pack-year smoker, who quit in 1974. As the patient tested positive for Epstein Barr virus (EBV) prior to lung transplant, an EBV quantitative polymerase chain reaction (PCR) test was ordered and revealed viremia with 28,700 copies (normal <250). Given his risk of infection from his immunosuppressive therapy, a computed tomography (CT) scan of the head, cultures, lumbar puncture, and chest x-ray were ordered. The CT revealed only microvascular ischemic changes consistent with the patient's age. The patient's B₁₂ level was 907 pg/mL (reference range, 211–911), and folate was 21.8 ng/mL (reference range, >5.4). The cerebrospinal fluid protein was 60 mg/dL, glucose was 131 mg/dL, and cultures for fungi, acid-fast bacilli, Cryptococcus, arbovirus panel, and West Nile were all negative. The cerebrospinal fluid antigen for Histoplasma was negative. In addition, blood and urine cultures, cytomegalovirus, and herpes PCR were negative. Magnetic resonance imaging revealed innumerable nonlytic lesions throughout all the osseous structures of the skull. A CT of the abdomen and pelvis demonstrated prominent paraaortic lymph nodes, multiple hypoattenuating hepatic lesions, and innumerable sclerotic lesions throughout the axial skeleton. A bone scintigraphy scan showed two small foci of uptake in the bilateral frontal regions and cortical uptake in the lower extremities.

At this junction, hematology/oncology was consulted. The patient's lactate dehydrogenase was 814 IU/L (reference range, 85–245). Serum protein electrophoresis did not reveal any monoclonal peaks. The patient's immunofixation profile was negative, and kappa and lambda chain quantification was unrevealing for gammopathy. A repeat EBV quantitative PCR revealed 601,000 copies of virus/mL. Bone marrow biopsy revealed a sheet-like plasmacytoid infiltrate composed of medium to large cells. Many cells had a large centrally placed nucleolus with a finely dispersed immature chromatin pattern consistent with a plasmablastic type morphology (Figure 1). These cells stained positive for CD138 (Figure 2) with patchy positivity for CD56. CD20 was diffusely negative. In situ hybridization showed strong EBV early RNA positivity, and in situ hybridization for kappa and lambda were negative. These findings were compatible with a diagnosis of a plasmablastic posttransplant lymphoproliferative disorder (PTLD). The patient received one dose of CHOP (cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisone). Due to increasing weakness from the therapy, the patient and the patient's family decided to pursue palliative care, and the patient died soon afterwards.

Figure 1.

High-power view (×200) of plasmacytoid infiltrate involving the bone marrow. Many of the nuclei are larger with an open chromatin pattern and prominent nucleoli consistent with a plasmablast morphology (arrows). There are also scattered smaller plasma cells with a clock-face chromatin and eccentrically placed nuclei.

Figure 2.

Immunohistochemical stain for CD138 showing strong positivity within the plasmacytoid infiltrate. ×40.

DISCUSSION

Numbness in the distribution of the mental nerve, or so-called numb chin syndrome, can be associated with both benign and malignant etiologies. To our knowledge, this is the first described case of numb chin syndrome as an initial presentation of malignancy in a transplant patient. It is still unclear how specific this clinical sign is for malignancy, the exact mechanism of effect on the mental nerve, if this sign is associated with a worse prognosis of malignancy, or if identification of a malignancy based on diagnostic workup done because of this sign would affect survival (16, 17).

In general, PTLD is a somewhat common but serious and potentially fatal complication of organ transplantation. PTLD accounts for about 20% of all malignancies following solid organ transplantation (18, 19). These cancers involve mostly B-cell components, but may also involve T cells or rarely natural killer (NK) cells (20). The cause is related to concurrent immunosuppression and EBV viremia (21). The underlying hypothesis is derived from an EBV-associated protein (LMP-1) that, in turn, stimulates tumor necrosis factor growth factors, leading to cell proliferation and transformation. Our patient received antithymocyte globulin, which bound to his T cells, inducing cytokine release initially before destroying the original T cells (22). The subsequent cytokine release undoubtedly led to the growth of EBV-infected B cells, marrow proliferation, and his final diagnosis of plasmablastic lymphoma (Figure 3). While most patients who develop PTLD do not have a history of treatment with antithymocyte globulin, immunosuppression is a key pathogenetic mechanism in the natural history of the disease, and it is highly probable that this contributed to his disease.

Figure 3.

Proposed mechanism through which antithymocyte globulin (ATG) can interfere with the immune response: (1) T-cell depletion in blood and peripheral lymphoid tissues through complement-dependent lysis and T-cell activation and apoptosis; (2) induction of B-cell apoptosis; (3) modulation of key cell-surface molecules (adhesion and chemokine receptors) that mediate leukocyte/endothelium interactions; (4) interference with dendritic cell (DC) functional properties (maturation and migration); and (5) induction of Treg and natural killer T (NK-T) cells. Reprinted with permission from Mohty, 2007 (22).

Plasmablastic lymphoma was first described in the late 1990s as an oral cavity lesion mainly seen in HIV-positive individuals (23). The disease usually develops from 35 to 55 years of age (24). This lymphoma has also been reported in HIV-negative patients, particularly those who have had immunosuppression. Since its original description, it has subsequently been described in the PTLD setting, albeit rarely. In 2003, the first case of plasmablastic lymphoma was recognized in a transplant patient; it presented as a cutaneous lesion (25). In 2008, plasmablastic lymphoma was classified by the World Health Organization as a subtype within the monomorphic category of PTLD. The histological findings of diffuse infiltrates, mitotic activity, and necrosis support the overlying description as a high-grade malignant lymphoma (26).

The incidence of PTLD depends on several factors, including which organ is transplanted, the EBV serostatus of both the donor and recipient, and the aggressiveness of the immunosuppression. The risk factors for development of this disorder can be further refined by the type of organ transplanted, time posttransplant, recipient age, and ethnicity (27, 28). Also, PTLD can develop at any point after the transplant, even as early as 2 months, but most cases occur within the first year of transplant. A French study of lung and heart transplant patients found that the median time for development of malignancy was >2 years. Typical presentations of PTLD include mononucleosis-type symptoms, palpable lymph nodes on exam, and symptoms of organ dysfunction. While our patient's natural history of PTLD was not unusual, we felt his initial presentation of numb chin syndrome without any of the typical signs or symptoms of PLTD was noteworthy.