A Rare Case of Brain Metastases in an Elderly Patient With Primary Pancreatic Cancer

Pancreatic adenocarcinoma is an extremely aggressive cancer with a low survival rate. Common sites for metastases include the liver and lungs, while brain metastases are considered extremely rare, especially in elderly patients. We present an elderly female patient who developed brain metastases 51 months after the initial diagnosis of pancreatic cancer and was treated with gross tumor resection, chemotherapy, and stereotactic radiosurgery. The treatment completely resolved her neurological symptoms but did not result in improved survival for this patient. The patient developed generalized tonic-clonic seizures, was diagnosed with leptomeningeal carcinomatosis, and died 5.5 months after tumor resection. The literature on pancreatic cancer with brain metastases is scarce, with limited guidelines for treatment strategies in this patient population. Adding this case report to the existing literature may provide additional guidance to clinicians managing patients with similar presentations.


Introduction
Pancreatic adenocarcinoma is aggressive cancer with an overall five-year relative survival rate of 9% [1] and a 7.6 per 100,000 incidence rate occurring in North America [2]. The most common sites for metastases from metastatic pancreatic cancer stage III and above include the liver, peritoneum, lungs, and bone [3]. Although the actual incidence of brain metastases from pancreatic cancer is unknown, they are considered extremely rare (0.1%-0.6%) [4,5], with an even lower incidence of antemortem cases reported in the literature [6,7]. This number is expected to increase due to improved treatments and prolonged survival. With only 28 brain metastasis from pancreatic cancer cases occurring before death reported in the literature to date [6], we report another rare case in an elderly female patient.

Case Presentation
A very active 80-year-old female patient, Karnofsky score 80, presented to the emergency department with worsening right upper extremity (RUE) and lower extremity (RLE) weakness, difficulty with fine motor tasks, but intact comprehension and speech. Neurological exam revealed intact sensation, but weakness in the RUE and RLE: 4/5 right grip, 3/5 biceps/triceps, 1/5 right deltoid, 3/5 dorsi-and plantar flexors, and 2/5 in hip flexion. The patient had stage IV (T3, N1, M1) pancreatic adenocarcinoma with brain metastases. Seven years earlier, the patient had undergone a Whipple procedure, followed by adjuvant chemotherapy and radiotherapy ( Figure 1), with excellent response and no known residual disease burden. Head computed tomography and brain magnetic resonance imaging (MRI) studies revealed right (18 x 18 mm) and left (31 x 30 mm) frontal lesions with peripheral enhancement and central necrosis with mild adjacent brain edema without midline shift, but a slight mass effect on the motor strip ( Figure 2).

Operation
The patient was admitted to the hospital and underwent oncologic staging which revealed no additional primary or metastatic lesions. The patient's case was presented to Tumor Board. The consensus of the Tumor Board was to proceed with surgery followed by adjuvant chemo-and/or radiosurgery, given the location of the tumor and the patient's overall status. Surgery was recommended to help improve the patient's neurologic deficit and functional status, which was not felt to improve as quickly with radiation therapy. All treatment options were reviewed with the patient, including no treatment, chemo/radiation alone, and debulking of the solitary symptomatic lesion vs. both lesions, but the patient opted for surgery on both to reduce the chance of requiring any future surgeries.
The patient was taken to the operating room and underwent a bifrontal craniotomy. A postoperative MRI scan ( Figure 3) showed gross total resections of both lesions with deceased mass effect and without residual enhancement. Pathologic analysis of the specimens demonstrated malignant cells consistent with metastatic adenocarcinoma of pancreatic primary exhibiting moderately to well-differentiated glandular structures with associated mucin and calcification. Immunostaining was positive for cytokeratin 7, epithelial membrane antigen, CDX2 (patchy), and CK20 (focal) without expression of thyroid transcription factor -1.

Postoperative course
Three weeks postoperatively, the patient had complete resolution of her right-sided weakness and no other neurological deficits. The patient underwent postoperative stereotactic radiosurgery (SRS) to both tumor bed cavities. The total target dose of 2,700 cGy was prescribed, 900 cGy in 3 fractions. The patient returned to the hospital 5.5 months after her tumor resection with generalized tonic-clonic seizures and severe shortterm memory issues. The patient was placed on levetiracetam and a brain MRI with contrast revealed leptomeningeal enhancement concerning leptomeningeal carcinomatosis. Given the patient's overall and rapid decline, the family and patient opted for palliative management, and she died within a few days.

Discussion
This case presents an elderly female patient with metastatic adenocarcinoma of pancreatic primary. Advanced age is a risk factor for developing pancreatic adenocarcinoma with cases primarily occurring in elderly patients with a median age of 70 [8]. Brain metastases from pancreatic adenocarcinoma most often occur in younger individuals with a median age of 58 and are often identified postmortem, with only 28 cases diagnosed before death ( Table 1) [6]. The median time between the pancreatic adenocarcinoma diagnosis and brain metastasis development ranges between 14 and 29 months [6,9]. The longest time was reported by Lemke et al. [10]. The authors presented a 48-year-old female patient diagnosed with a right cerebellum metastasis 65 months after the diagnosis of pancreatic adenocarcinoma, which was successfully resected followed by radiotherapy with no local or distant recurrences at the 17-year follow-up. In our case, the patient's primary cancer was successfully managed for 51 months until the development of brain metastases and leptomeningeal carcinomatosis. There are only a few reports of brain metastasis and leptomeningeal disease in patients with pancreatic cancer [11].  BM -brain metastasis; BSC -best supportive care; D -days; DP -distal pancreatosplenectomy; Dx -diagnosis, LN -lymph node; M -months; MSTmedian survival time; N -no; Res -resection; OS -overall survival time; PD -pancreaticoduodenectomy; RT -radiotherapy; S -synchronous; Txtherapy; Y -years; Y -yes; yo -years old.
The The optimal treatment strategies for pancreatic adenocarcinoma patients with brain metastases are still debatable, but surgical resection is generally recommended, especially for cystic lesions larger than 3 cm and located in eloquent areas [24]. In the recently published Radiation Therapy for Brain Metastases Guidelines by the American Society for Radiation Oncology, SRS alone is conditionally recommended and has lowquality of evidence for patients with intact brain metastases measuring between 2 and 4 cm in diameter [25]. Given the tumor sizes, symptomatology and remission of the primary tumor, surgical resection, and adjuvant SRS was considered feasible treatment strategy for this patient. Overall, the patient did well postoperatively and recovered full strength. In hindsight, a single craniotomy to resect the symptomatic lesion would have been a less invasive strategy, but this was a very active woman who wished to return to her baseline functional status. Surgery performed seemed an appropriate course of action to address her presentation.
The median survival time was 11 months, and the 1-year local control rate was 73% in a study that evaluated tumor bed SRS after resection of brain metastases [26]. The authors noted that a lower maximum dose and SRS delay (>3 weeks) were associated with increased local recurrence. In our case, the patient survived 58 months after the initial diagnosis. Although a full resolution of her neurological symptoms was achieved for a short period of time following gross total resection and adjuvant SRS, it did not result in an overall survival benefit. According to a literature review of the 28 reported antemortem cases so far [6], the survival from diagnosis of brain metastases ranges from two weeks to more than 10 years for surgical treatment and from three days to more than one year for treatments that included best supportive care, chemotherapy and radiation therapy.

Conclusions
We report an 80-year-old female patient treated with a gross total resection and adjuvant radiosurgery for two bilateral frontal area metastases from pancreatic cancer, which completely resolved her neurological symptoms, but did not result in improved survival for this patient. The literature on pancreatic cancer with brain metastases is scarce, with limited guidelines for treatment strategies in this patient population. Adding this case report to the existing literature may provide additional guidance to clinicians managing patients with similar presentations.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.