EP745 - Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) of the colon

Purpose/Background: Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the colon are rare malignancies composed of neuroendocrine (NE) and non-NE components, each representing at least 30% of the tumor with adenocarcinoma being the most common NE element. Xu et al. reported an incidence of 1.225 per 1,000,000 person-years between 2000-2019, with a rising trend. The management remains poorly defined due to limited data. We present the first reported case of colonic MiNEN in a patient receiving tofacitinib (Xeljanz), a Janus kinase (JAK) inhibitor.

Methods/Interventions: The patient is an 80-year-old female with RA, hypertension, and hyperlipidemia who presented with several months of progressive right lower quadrant pain, constipation, and poor oral intake. CT imaging revealed an appendiceal mass, an ascending colon "apple-core" lesion, porta hepatis mass, and a right inguinal hernia. After workup, she underwent diagnostic laparoscopy, exploratory laparotomy, drainage of intraabdominal abscess, right colectomy with extended lymphadenectomy, right salpingo-oophorectomy, and right inguinal herniorrhaphy.

Results/Outcomes: Pathology demonstrated a 3.5 cm ulcerated, invasive, poorly differentiated MiNEN of the ascending colon composed of high-grade large-cell neuroendocrine carcinoma (NEC) (60%) and poorly differentiated adenocarcinoma (40%). Both components showed MLH1/PMS2 loss, intact MSH2/MSH6, and a BRAF V600E mutation. Six of 22 lymph nodes were positive for metastasis (3 NE and 3 non-NE). The appendiceal lesion represented perforated appendicitis with periappendiceal abscess; both appendix and ovary were negative for malignancy.

Conclusion/Discussion: MiNENs are diagnosed histopathologically, after surgical resection. Immunohistochemical markers for the NE component include synaptophysin, chromogranin, INSM1, CD56, and NSE. No standardized grading system exists, and tumor behavior is guided by the most aggressive element. AJCC TNM criteria are used for staging. The NEC component most commonly metastasizes, though dual-component spread may occur. Treatment for MiNENs can be difficult due to the rare nature of these tumors. Management involves a multidisciplinary approach, targeting the dominant component. NECs are generally treated with etoposide-cisplatin, while adenocarcinomas utilize 5-FU-based regimens. In this case, therapy was adjusted for the patient's mismatch repair deficiency and BRAF mutation.

Preoperatively, colonoscopy revealed a friable nonobstructive ascending colon mass. Imaging showed metastatic mesenteric lymphadenopathy without distant disease. Intraoperatively, dense adhesions and bulky nodal disease necessitated conversion to open surgery and D3 lymphadenectomy. Her chronic pain was later attributed to perforated appendicitis, likely blunted by immunosuppression from tofacitinib. JAK inhibitors have been linked to increased infection risk and possibly malignancy, potentially influencing both her presentation and disease course.

This case represents the first documented MiNEN of the colon in a patient on tofacitinib. It highlights the diagnostic challenges and therapeutic complexity of MiNEN, particularly in immunosuppressed individuals. Early recognition, extensive surgical resection, and multidisciplinary management are essential for optimal outcomes in this rare malignancy.

1x CDX2 Stain
Blue Arrow - LCNEC; Red Arrow - Poorly Differentiated Adenocarcinoma; Both positive
1x SynapStain
Green Arrow - NonNeoplastic Mucosa; Blue Arrow - LCNEC Component; Red Arrow - Poorly Differentiated Adenocarcinoma