Case Presentation: A 48-year-old female with no significant medical history presented to an outside hospital with epigastric pain of 3 weeks duration. The pain was constant and severe, associated with nausea, vomiting and a 20 lb. weight loss. Serum lipase was elevated at 1135 U/L (nl 8-78). An Abd US revealed multiple hepatic lesions without pancreatic involvement. She was discharged home with symptom management. As her pain persisted, she presented to our ER 3 days later. On exam, vital signs and physical were unremarkable except for mild tenderness in the epigastrium with deep palpation. Initial laboratory results included: TBI 0.5 (0.1-1.2 mg/dL), ALP 139 (38-126 U/L), AST 92 (<36 U/L), ALT 53 (<46 U/L), Lipase 719 (8-78 U/L), AFP 1.1 (0-7.5 ng/mL), CA 19-9 59.7 (0-41.3 U/mL), elevated CEA 5.3 ng/mL and Chromogranin A 236 (0-39 ng/mL). CT imaging revealed several poorly marginated hypodense lesions in the liver, a poorly defined hypodensity at the anterior pancreas head/neck measuring 1.6cm x 1.3cm, mild pancreatic duct and CBD dilation, numerous enlarged portacaval nodes, and a few pulmonary nodules. Liver pathology revealed a poorly differentiated, high grade neuroendocrine carcinoma (Ki67 >90%, Synaptophysin positive) with small cell features, thought to be of pancreatic origin. Patient received cisplatin + irinotecan and was discharged with oncology follow-up. Due to tumor progression, the therapy was later switched to docetaxel. The patient was readmitted approximately 7 months following initial presentation, with the patient expiring secondary to disease burden.
Discussion: Neuroendocrine neoplasms (NENs) are rare, accounting for only 0.46% of gastrointestinal or bronchopulmonary malignances, and are heterogenous in their morphology, proliferation rate, anatomical location and clinical behavior. Classification has evolved to better differentiate these tumors to guide treatment and prognostication. The 2016 World Health Organization classification system categorizes NENs as either neuroendocrine tumors (NETs/ well differentiated NENs) or neuroendocrine carcinomas (NECs, large or small subtype/ poorly differentiated NENs) based primarily on morphology as well as proliferation rate (Ki67 index, where >20% denotes high grade tumor proliferation). Survival for well differentiated low-grade NETs can be years. Among NECs however, the prognosis is more worrisome; A higher Ki67 index is specifically correlated with worse survival. Recent studies suggest that platinum based therapies, which are first-line treatments for NECs, may not work as well if the Ki67 index is between 20-55%. Median survival for poorly differentiated NECs is alarming: 34 months with local disease, 14 months with regional disease, and 5 months with distant metastasis, with the majority of patients having metastasis on diagnosis.
Conclusions: Neuroendocrine neoplasms (NENs) need to be classified by histopathology (including morphology and proliferation grade via Ki67 index) in order to guide therapeutic options and for prognostication. Early diagnosis, proper histopathologic and clinical classification is critical.
This case with its extraordinarily high Ki67 index (>90%) highlights an aggressive sub-type of an already rare disease, making it a zebra of a zebra.