Paraneoplastic syndrome in neuroendocrine breast cancer: A case report

Abstract

Background

Paraneoplastic syndromes are rare manifestations of underlying malignancies, most commonly small cell lung cancer and invasive ductal carcinoma of the breast.

Case

We present a case of anti‐AMPA receptor paraneoplastic limbic encephalitis, a specific paraneoplastic syndrome, in a woman with neuroendocrine breast cancer. Her condition improved with surgical resection and chemotherapy.

Conclusion

This is the first known case of anti‐AMPA receptor paraneoplastic limbic encephalitis in a patient with primary neuroendocrine breast cancer.

1. INTRODUCTION

Paraneoplastic neurological disorders (PND) are characterized by neurological symptoms associated with an underlying cancer.1 Mechanistically, a cancer may trigger an immune response that cross‐reacts with the nervous system. Paraneoplastic limbic encephalitis (PLE), a specific PND, affects the medial temporal lobes, amygdala, and orbitofrontal cortex and is characterized by acute or subacute personality change, seizure, or memory loss.2 Small cell lung cancer (SCLC) accounts for over 50% PLE cases, with breast cancer (most often ductal type) making up less than 8%.3 Although neuroendocrine cancers are known to be associated with PND, there is only one known case associated with a primary tumor of the breast.4

2. CASE

A 60‐year‐old female with a 2.2 × 2.1 cm, clinical stage Iib (T3N0M0), grade 3 neuroendocrine carcinoma of the right breast (ER‐/PR+/Her2‐ / E‐Cad+/CK7+/Synaptophysin+/CD56+/Mammoglobulin‐/GCD‐/FP‐15‐/Chromogranin‐) presented with altered mental status. On exam, she was only oriented to self and recalled 0/3 objects at 3 minutes. The remainder of her exam was normal. After unrevealing neurologic, metabolic, infectious, and metastatic workups including inpatient computed tomography (CT) and magnetic resonance imaging (MRI) head, inpatient electroencephalogram (EEG), and outpatient CT chest/abdomen/pelvis and bone scan 2 weeks prior to presentation, cerebrospinal fluid demonstrated high titers, 1:512, of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor avid autoantibodies consistent with PLE. Surgical oncologists performed a right total mastectomy with sentinel lymph node biopsy. With adjuvant doxorubicin (60 mg/m² × 4 cycles) and cyclophosphamide (600 mg/m² × 4 cycles) followed by paclitaxel (175 mg/m² × 4 cycles), she improved from needing one‐to‐one sit‐in care to living independently. She has since started tamoxifen (20 mg/daily) and has plans for future radiation therapy. She continues to do well with a normal mental status exam at 6 months of follow up.

3. DISCUSSION

PND is a rare disease. From all cases of PND and breast cancer, 3.6% are related to PLE.5 From all cases with PLE, breast cancer is the second most common tumor, representing 4.5% to 8% of all cases.3 The association of PND with neuroendocrine breast tumors, although rare, has been previously reported.6 However, the association with PLE is largely undescribed. There are a variety of other PNDs associated with breast cancer (see Table 1).

Table 1.

Paraneoplastic neurological disorders in breast cancer

	Symptoms	Antibodies	Antibody Detection, %	Underlying Breast Cancer, %
Cerebellar degeneration	Ataxia	Yo	367	237, 8, 9
	Nystagmus	CRMP5
	Vertigo	Hu
		Zic4
		mGluR1
Limbic encephalitis	Altered mental status	Ma	603	63, 10
	Psychiatric disturbance	CRMP5
	Seizure	Hu
	Memory loss	AMPA
		NMDA
		VGKC
Opsoclonus‐myoclonus syndrome	Muscle spasm	Ri	811	612
	Tremor	Yo
	Hypotonia	Hu
	Involuntary saccades	NMDA
Retinopathy	Worsened visual acuity	Recoverin	4413	3114
	Photosensitivity	Enolase
		Transducin‐beta
Stiff person syndrome	Generalized rigidity	Amphiphysin	2015	9
	Muscle spasm	GAD
Sensory peripheral neuropathy	Limb paresthesia	Hu	8516	117
	Hyporeflexia	Rho
		Ri

Because symptoms may mimic other more common conditions, PLE is often a late diagnosis after exhaustive work up for infectious, toxic, metabolic, psychiatric, endocrine, autoimmune, and neurodegenerative causes. In 65% of cases, PLE is the presenting symptoms of malignancy.10 Even with known malignancy, antibodies are found in 60% of patients, and MRI findings in only 50%.3 Diagnosis therefore considers symptoms, and the results of a cancer work‐up, lumbar puncture, imaging, and EEG.

Because PLE is a cancer‐stimulated immune response, primary treatment targets the cancer, not the immune system. In one study, tumor treatment improved neurological symptoms in 73% of patients. Patients only receiving corticosteroids, intravenous immunoglobulin (IVIg), or plasma exchange (PLEX), did not improve.3 Rituximab is a novel immunotherapy that reduces central (versus peripheral) nervous system antibodies. It has thus far been tested against NMDA PLE and may soon prove beneficial for other PND.18 Treating the cancer, versus dampening the immune system, also combats relapses, a hallmark of AMPA PLE (0% vs more than 50%). Even after cancer treatment, patients may have long‐lasting deficits. In AMPA PLE, 71% of patients responded to cancer treatment, with only 32% of responders having a complete response.19, 20

Because of rapid tumor treatment, this patient returned to her functional baseline, with only minor deficits in attention and short‐term memory revealed on neuropsychiatric testing.

4. CONCLUSION

PLE is a rare but dangerous condition associated with breast cancer. It is even less commonly associated with neuroendocrine breast cancer. Although rare, PLE is difficult to both detect and treat and must remain on the differential for any patient with new neurological or psychiatric symptoms.

CONFLICT OF INTEREST

The authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or nonfinancial interest in the subject matter or materials discussed in this manuscript.

AUTHORS' CONTRIBUTIONS

All authors had full access to the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. Conceptualization, E.L.L., L.I.R., M.D.B.; Methodology, E.L.L., L.I.R., J.P., P.A.P.; Investigation, E.L.L., L.I.R., M.D.B., J.P., P.A.P.; Formal Analysis, E.L.L., L.I.R., P.A.P.; Resources, E.L.L., L.I.R., M.D.B.; Writing‐Rriginal Draft, E.L.L., L.I.R., M.D.B., J.P., P.A.P.; Writing‐Review & Editing, E.L.L.; Visualization, E.L.L., L.I.R.; Supervision, J.P., P.A.P.

ETHICAL STATEMENT

1. This patient gave informed consent for this case to be published.

2. This case report does not require IRB approval, as it only includes one patient

Levenbaum E, Ruffolo LI, Balceniuk MD, Peacock J, Prieto PA. Paraneoplastic syndrome in neuroendocrine breast cancer: A case report. Cancer Reports. 2019;2:e1162. 10.1002/cnr2.1162