An Autoimmune-Based, Paraneoplastic Neurologic Syndrome Following Checkpoint Inhibition and Concurrent Radiotherapy for Merkel Cell Carcinoma: Case Report

Abstract

Purpose:

Merkel cell carcinoma is highly sensitive to both radiation and immunotherapy. Moreover, concurrent radioimmunotherapy may capitalize on anti-tumor immune activity and improve Merkel cell treatment response, although an enhanced immune system may cross-react with native tissues and lead to significant sequelae.

Methods:

Here we present a case study of a patient with metastatic Merkel cell carcinoma treated with radiotherapy concurrent with pembrolizumab.

Results:

After radioimmunotherapy, he developed sensory neuropathy, visual hallucinations, and mixed motor neuron findings. Neurologic dysfunction progressed to profound gastrointestinal dysmotility necessitating parenteral nutrition and intubation with eventual expiration.

Conclusion:

This case represents a unique autoimmune paraneoplastic neurologic syndrome, likely specific to neuroendocrine tumors and motivated by concurrent radioimmunotherapy. Recognition of the potential role of radioimmunotherapy may provide an advantage in anticipating these severe sequelae.

Introduction

Merkel cell carcinoma (MCC) is an aggressive radiosensitive cutaneous neuroendocrine malignancy occurring in older adults. Prognosis is poor in metastatic MCC, and management includes radiotherapy (RT). Recent phase II data have shown >50% response rates with checkpoint inhibition for metastatic MCC leading to FDA approval of avelumab and pembrolizumab [1-4]. Hypotheses for these promising responses to immunotherapy include the clonal integration of the Merkel cell polyomavirus in up to 80% of cases, as well as a high ultraviolet light-driven mutational burden in tumors without polyomavirus [5, 6]. Multiple observations corroborate the clinical importance the immuno-oncologic axis in MCC, including a reduction in MCC-specific survival with systemic immunosuppression, a reduction in overall survival with high viral load, and an improvement in overall survival with high intratumoral cytotoxic T cells [7, 8].

Interestingly, however, even this highly immunogenic tumor can become resistant to immunotherapy, and in this setting, concurrent radioimmunotherapy may restore therapeutic efficacy [9]. There is ample evidence that radiotherapy may enhance host anti-tumor immunity and the efficacy of immunotherapy in many diverse tumors [10]. Mechanisms of this synergy include radiation-induced generation of neoantigens and neoepitopes, radiation modulation of the T-cell receptor repertoire, and anti-cancer tumor microenvironmental changes secondary to radiation [11-15]. However, while these data are promising, a therapeutically enhanced immune system, further bolstered by radiotherapy, can also attack native tissues, as immune augmentation is not specific to malignant cells and can obstruct host efforts at maintaining self-tolerance. Such off-target T-cell activation as a result of immunotherapy has been frequently observed as a low-grade toxicity of the skin, lungs, or gastrointestinal system, although severe toxicities of other organ systems have been reported [16, 17]. In this report, we present a patient with metastatic MCC. After radioimmunotherapy for refractory disease, the patient acutely developed a severe, widespread gastrointestinal plexus neuropathy refractory to immunosuppression leading to fatality.

Case and Outcomes

A 74-year-old Caucasian male with a history of stage I MCC of the dorsal right finger presented with recurrent disease of the right medial volar forearm involving the subdermal lymphatics without axillary adenopathy (see full treatment outline in Table 1). The forearm was treated with 9 MeV electron beam radiotherapy with 1 cm bolus to a dose of 50.4 Gy in 28 fractions (prescribed to 90% isodose line) with concurrent carboplatin and etoposide based on available data at that time [18].

Table 1.

Treatment course and timeline.

Time from Diagnosis (Months)	Treatment	Dose	Target
1	Ray amputation	N/A	Right long finger
13	Electron beam radiotherapy	50.4 Gy in 28 fractions	Right forearm
13	Carboplatin	AUC 5	Systemic concurrent with RT
13	Etoposide	100 mg/m2	Systemic concurrent with RT
21	Nodal dissection	N/A	Right axilla
25	3D-CRT	60 Gy in 33 fractions	Right axilla
25	Carboplatin	AUC 5	Systemic concurrent with RT
25	Etoposide	100 mg/m2	Systemic concurrent with RT
30	IMRT twice-daily	45 Gy in 30 fractions	Right forearm; proximal upper extremity
30	IMRT twice-daily	45 Gy in 30 fractions	Right upper abdominal quadrant nodule, Nodule inferior to right breast tissue
32	Pembrolizumab	2 mg/kg	Systemic
33	IMRT	30 Gy in 5 fractions	Right anterior chest, right axilla, right back
33	Pembrolizumab	2 mg/kg	Systemic concurrent with RT
40	IMRT	24 Gy in 3 fractions	Right shoulder
40	Pembrolizumab	2 mg/kg	Systemic concurrent with RT

Abbreviations: 3D-CRT (three-dimensional conformal radiotherapy); IMRT (intensity-modulated radiotherapy); AUC (area under the curve).

Seven months after treatment, interval PET/CT demonstrated right axillary nodal avidity, confirmed pathologically in 1/33 nodes after dissection. Subsequent post-operative interval PET/CT showed recurrent right axillary gross disease. This was treated with definitive photon-based three-dimensional conformal RT for a cumulative dose of 60 Gy in 33 fractions with concurrent carboplatin/etoposide. Chemotherapy was held for one week during admission for neutropenic fever.

Three months post-chemoradiotherapy, he had biopsy-proven recurrent MCC in the right forearm inferior to the antecubital fossa and the right proximal upper extremity. To reduce the risk of re-irradiation, he was treated with intensity-modulated radiotherapy (IMRT) twice-daily to a dose of 45 Gy in 30 fractions. During IMRT, he was diagnosed with a cutaneous MCC nodule on the lateral aspect of the right upper abdominal quadrant and a synchronous nodule at the inferior border of right breast tissue. These foci were treated with IMRT twice-daily to a dose of 45 Gy in 30 fractions.

Two months after IMRT, he recurred with gross cutaneous nodules on the right chest and axilla, all within the radiation portal of previous treatments. He received two doses of pembrolizumab based on a phase II study [2]. After continued local progression, he was treated with short-course high-dose IMRT to 30 Gy in 5 fractions concurrent with a third dose of pembrolizumab, since short-course high-dose RT had been reported to achieve durable palliation and an abscopal effect in metastatic MCC as well as a need to reduce the risk of re-irradiation [19]. His lesions responded well to RT, but all tumor-directed therapy was held for three months due to transfusion-dependent anemia, thrombocytopenia, red cell aplasia, and pneumonitis managed with prednisone. He subsequently relapsed with cutaneous lesions at the right posterior shoulder, right mid-scapula, and right upper abdomen, as well as right supraclavicular nodal involvement. Since he was not a candidate for chemotherapy due to thrombocytopenia and because he initially responded well to pembrolizumab, he received concurrent radioimmunotherapy with 24 Gy in 3 nonconsecutive fractions of 9 MeV electron beam with 1.5 cm bolus (prescribed to 95% isodose line) to the right shoulder and one dose of pembrolizumab.

On the last treatment day, he reported new shooting neuropathic pain of the right upper extremity and was prescribed gabapentin and hydrocodone/acetaminophen. Three days later, he was admitted with visual hallucinations, deteriorating mobility, and constipation. His neurological exam was notable for diffuse myoclonus, dysmetria, dysdiadochokinesia, and atrophy of the left interossei with fasciculations of the first dorsal interosseous. He had hyperreflexia in the left upper extremity (right upper extremity was bandaged and not assessed), as well as hyperreflexia with non-symmetric lower extremity clonus (left lower extremity: 15+ beats; right lower extremity: 3 beats).

Brain MRI with contrast was unremarkable except for a small focus of enhancement within the anteromedial left cerebral peduncle lacking T2 hyperintensity or edema; this was stable compared to previous scans and interpreted as artifactual. Spine MRI was also unrevealing, and electroencephalography showed mild to moderate generalized, non-specific cerebral dysfunction. Cerebrospinal fluid was notable for mildly elevated total protein, albumin, and IgG-Index (0.85) without oligoclonal immunoglobulin. Mayo clinic laboratories CSF paraneoplastic autoantibody panel was negative.

After spontaneous improvement with supportive care and discontinuation from medications with potential to exacerbate his symptoms, steroids were deferred, and he was discharged. However, he was re-admitted three days later for intractable emesis without bowel movement concerning for small-bowel obstruction. Abdominal CT showed circumferential thickening of the distal esophagus and marked gastric distension to the second portion of the duodenum, which was confirmed by upper gastrointestinal series (Figure 1). However, esophagogastroduodenoscopy showed no evidence of stricture, mass, ulcer, or fixed luminal obstruction in the esophagus, duodenum, or jejunum.

Figure 1.

Gastric dysmotility evaluated by axial CT abdomen showing A) circumferential thickening in the distal esophagus (arrow) and B) gastric distention; C) upper GI series showing multifocal esophageal narrowing.

The patient’s gastric dysmotility and emesis failed to improve with 70 mg IV methylprednisolone. Worsening dysphagia necessitated nasogastric feeding, which was poorly tolerated and transitioned to total parenteral nutrition. Following initiation of total parenteral nutrition, he developed methicillin-resistant staphylococcus aureus bacteremia. Continued emesis, in conjunction with oropharyngeal dysmotility, required airway protection with temporary intubation lasting one day following aspiration and development of aspiration pneumonia. After eight cumulative weeks hospitalization, the patient failed to regain bowel function and was unable to tolerate tube feeds. After goals of care reassessment, the patient voiced desire for discharge to home hospice. He shortly expired thereafter.

Discussion

In this report, we present a patient who presented with profound, progressive, complex, widespread neurologic dysfunction after palliative concurrent radioimmunotherapy. This dysfunction manifested on the final day of radioimmunotherapy with non-localizable upper and lower motor neuron dysfunction and sensory neuropathy, without imaging correlates, that progressed to fatal enteric plexus neuropathy refractory to immunosuppression. Although enteric neuropathy was apparent on imaging, no anatomic abnormalities were identified endoscopically.

Taken together, these findings suggest an autoimmune, paraneoplastic neurologic syndrome specific to MCC and potentially motivated by combination radioimmunotherapy. Similar autoimmune paraneoplastic neurologic syndromes have been reported in metastatic MCC treated with immunotherapy, but never in the context of radioimmunotherapy [20, 21] [22] . Combined checkpoint inhibition, rather than single-agent immunotherapy, is linked to an increased risk of immune-related adverse events, suggesting a proportional relationship between immunostimulation and toxicity [23]. RT, as an immunomodulator, can generate endogenous anti-tumor vaccines through immunogenic cell death, as tumor antigens are made available by radiotherapy for immune-stimulating presentation [24]. Because of this property, concurrent radioimmunotherapy may be plausibly employed to attempt to induce the abscopal effect, whereby distant tumor foci regress after local RT due to anti-tumor immunity [25-27]. However, just as efficacy is increased by synergism, combination radioimmunotherapy may also increase immune-related toxicity, such as that manifested in our patient [28]. Nonetheless, we cannot exclude the possibility that these manifestations were due to immunotherapy alone and coincidentally occurred by chance at the end of radiotherapy. Furthermore, it is also possible that these effects were simply a result of a paraneoplastic syndrome induced by the cancer itself and unrelated to either treatment. Further pre-clinical and clinical study of the interaction between radiation, immunotherapy, and MCC is necessary to more conclusively establish causality and offer evidence-based recommendations.

Due to multiple overlapping courses of radiation, we retrospectively reviewed cumulative dosimetry to evaluate the possibility of radiation-induced ileus or enteric toxicity (Table 2). Cumulative doses to organs at risk are well within normal tissue dose limits, as further illustrated in Supplemental Figures 1-3, lessening the likelihood of this diagnosis [29-33].

Table 2.

Summary of radiation treatment courses with dose to organs at risk per series and cumulative dose along with reference thresholds [29-33].

Course	Structure	Max point dose (Gy)		Volumetric max dose* (Gy)		Dose to >195 cc (Gy)		Volume receiving >45 Gy (cc)		Volume receiving >35 Gy (cc)		Volume receiving >30 Gy (cc)
		Patient	Ref.	Patient	Ref.	Patient	Ref.	Patient	Ref.	Patient	Ref.	Patient	Ref.
1	Stomach	0	54	0	54	-	-	0	<50	-	-	-	-
	Esophagus	0	74	0	74	-	-	0	-	0	-	0	-
	Small bowel	0	50	0	50	0	45	0	20	0	150	0	200
	Peritoneal cavity	0	-	-	-	0	45	0	195	-	-	-	-
2	Stomach	2.9	54	2.5	54	-	-	0	<50	-	-	-	-
	Esophagus	5.23	74	4.68	74	-	-	0	-	0	-	0	-
	Small bowel	1.36	50	1.34	50	1.22	45	0	20	0	150	0	200
	Peritoneal cavity	4.65	-	-	-	0.73	45	0	195	-	-	-	-
3	Stomach	38.95	54	38.08	54	-	-	0	<50	-	-	-	-
	Esophagus	12.21	74	12.09	74	-	-	0	-	0	-	0	-
	Small bowel	44.98	50	43.94	50	28.97	45	0	20	42.77	150	148.9	200
	Peritoneal cavity	46.82	-	-	-	37.2	45	1.59	195	-	-	-	-
4	Stomach	5.63	54	5.32	54	-	-	0	<50	-	-	-	-
	Esophagus	15.28	74	14.41	74	-	-	0	-	0	-	0	-
	Small bowel	3.78	50	3.69	50	0.83	45	0	20	0	150	0	200
	Peritoneal cavity	20.24	-	-	-	2.45	45	0	195	-	-	-	-
5	Stomach	0	54	0	54	-	-	0	<50	-	-	-	-
	Esophagus	0	74	0	74	-	-	0	-	0	-	0	-
	Small bowel	0	50	0	50	0	45	0	20	0	150	0	200
	Peritoneal cavity	0	-	-	-	0	45	0	195	-	-	-	-
Cumulative	Stomach	45.56	54	44.18	54	-	-	<0.01	<50	-	-	-	-
	Esophagus	25.94	74	23.74	74	-	-	0	-	0	-	0	-
	Small bowel	47.55	50	46.51	50	29.85	45	0.3	20	54	150	188	200
	Peritoneal cavity	-	-	-	-	38.65	45	24	195	-	-	-	-

Course 1: electron beam radiotherapy 50.4 Gy in 28 fractions to right forearm. Course 2: 3D-CRT 60 Gy in 33 fractions to right axilla. Course 3: IMRT twice-daily 45 Gy in 30 fractions to right forearm, right upper abdominal nodule, and to nodule inferior to right breast tissue. Course 4: IMRT 30 Gy in 5 fractions to right anterior chest, right axilla, right back. Course 5: En face electrons 24 Gy in 3 fractions to right shoulder.

As a neuroendocrine tumor sharing a neural crest embryological origin with enteric neurons, MCC may express of neural antigens that increase the risk of paraneoplastic neurologic autoimmunity [34-37]. Immunologic recognition of neural antigens presented by tumor cells may be fueled in the setting of checkpoint blockade, which suppresses immune regulatory pathways that normally function to promote self-tolerance, leading to neurologic sequelae [38]. Similar autoimmune paraneoplastic neurologic syndromes have been reported in melanoma and small cell lung cancer, which share similar neural embryological origins [39, 40]. However, a humoral mechanism of disease, either primary or in addition to cellular autoimmunity, cannot be ruled out in this patient, although typical MCC paraneoplastic autoantibodies were undetectable [41].

Recommendations

Notably, our patient reported a globus sensation roughly three months after initiating radioimmunotherapy. This symptom possibly heralded impending neurologic toxicity progressing to motility failure, suggesting that sentinel symptoms may afford early diagnosis and treatment before irreversible loss of gut function. Similarly, his constipation worsened during radioimmunotherapy. Although this worsening was attributed to opioids at the time, this symptom may also have signaled for potential intestinal obstruction and enteric neuropathy. As autoimmune paraneoplastic syndromes continue to be studied in MCC treated by immunotherapy, early clinical signs such as these may serve as markers of impending disease before irreversible neurologic dysfunction and plexus destruction.

Conclusion

Diagnosing paraneoplastic autoimmunity is a unique challenge. Recognition of the potential role of radioimmunotherapy of promoting this syndromic paradigm may provide an advantage in anticipating and treating these severe sequelae. A strong level of clinical suspicion when treating neuroendocrine tumors is warranted. Future studies of radioimmunotherapy should carefully consider immune-related adverse events including autoimmune paraneoplastic syndromes.