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A 57-year-old woman with long-term cirrhosis and ulcerative colitis presented to an emergency department with a hugely distended and painful abdomen. Twenty years earlier she had declined to have a colonoscopy for suspected inflammatory bowel disease (IBD). Now, a CT scan revealed that the untreated IBD was the least of her problems. Saud A. Al Buthi, MD, of King Saud bin Abdulaziz University for Health Sciences in Riyadh, Saudi Arabia, and colleagues described the rest of the story in their report in .

The woman explained that for the past 2 weeks, her stomach pain has been accompanied by alternating bouts of constipation and loose bowel movements. On further questioning, clinicians learned that she has had no appetite for food, and was losing weight over the past 2 years. Asked about her medical history, she described one isolated incident 20 years earlier of severe abdominal pain with diarrhea and rectal bleeding; due to suspected IBD, clinicians advised a colonoscopy, but the patient declined and thus was neither diagnosed nor treated.

Physical Exam, Lab Tests, CT Findings

Although the patient's vital signs were normal, she appeared malnourished and dehydrated. Her distended abdomen was somewhat tender on palpation, and with "shifting dullness" on percussion.

Laboratory test findings at admission were within normal ranges, except for somewhat lower levels of hemoglobin (9.7 g/dL vs a normal range of 12.1 to 15.1 g/dL) and sodium (117 mEq/L vs 135 to 145 mEq/L), and tumor markers showing elevated levels of CA-125 (233 U/mL vs normal levels <35 U/mL).

CT of the abdomen and pelvis confirmed significant distension of the large bowel -- the diameter of the cecum was 8.5 cm, decreasing to a short stricture of 2 cm at the mid-transverse colon and another stricture of 5 cm at the distal descending colon. The scan also showed a polypoid mass located on the medial colonic wall a short distance from the descending colon.

Al Buthi and co-authors noted that several findings suggested IBD, particularly ulcerative colitis (UC), including evidence of inflammation marked by irregular mucosal thickening, hyper-enhancement, and fat stranding adjacent to the colon, as well as the .

Cirrhosis, HCV

The scan also showed that the patient's liver was cirrhotic, with evidence of multiple hypodense micro-nodules and thrombosis affecting the right hepatic vein.

Clinicians were concerned about the finding of cirrhosis, and ordered additional lab tests, which indicated the presence of hepatitis C virus (HCV), categorized as Child-Pugh score B with ascites and hepatic vein thrombosis.

A determination was therefore made, based on the findings of co-morbid liver cirrhosis and bowel obstruction, that the patient's condition was unstable and she was admitted to the intensive care unit (ICU).

Surgery, Pathology

Clinicians planned surgery to divert the stoma, temporarily relieve the obstruction, and allow for biopsies of the lesions in order to offer the patient a complete diagnosis and stage of the cancer. They also hoped to strengthen the patient clinically in preparation for "definitive resection, and proper planning of the extent of resection."

The pathology report for the biopsy specimen from the transverse colon noted large cells with reflecting adenocarcinoma and neuroendocrine carcinoma morphology. Immunohistochemical staining revealed that over half of the tumor was positive for synaptophysin and CDX2, with a Ki67 index of 75%. Additionally, CK20 positivity was noted in more than 40% of the carcinoma cells.

Diagnosis: Mixed Neuroendocrine Non-neuroendocrine Neoplasms

Thus, the biopsy findings reflected poorly differentiated mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) in a background of active chronic colitis, which confirmed the UC diagnosis.

Additionally, an MRI of the liver lesions taken to exclude metastasis confirmed a redemonstration of the cirrhosis, with no evidence of any lesions of concern.

The patient was started on hydrocortisone as well as supportive medical care while in the hospital, but there was no evidence of significant improvement. After consultation with the tumor board committee, the decision was made to proceed with high-risk surgery for total colectomy, given the patient's UC and multiple malignant lesions on the transverse and descending colon.

Examination of the colon revealed one stricture at the transverse colon and another two masses at the descending colon. The team then performed a total colectomy with end-ileostomy, and sent the specimens for pathologic examination.

The report identified a multifocal colonic tumor with three distinct masses. The mass located at the transverse colon at the location of the stricture showed MiNEN of poorly differentiated neuroendocrine carcinoma, Ki67 >70%, and poorly differentiated signet cell carcinoma located within 1 mm from the serosal surface.

Of the remaining two masses at the descending colon, one was poorly differentiated signet cell carcinoma and the other was moderately differentiated adenocarcinoma. The pathologic final staging was mpT3 N2b M0.

Post-Surgery Developments and Follow-up

Following surgery, the patient's overall condition improved and she was discharged from the ICU and advised to return for monitoring of her liver cirrhosis. Clinicians agreed that her co-morbidities and performance status put her at high risk for adjuvant chemotherapy.

Two weeks after discharge, she returned to the clinic where a physical examination indicated that her surgical incisions had healed completely. After receiving an explanation of her advanced disease status, the patient and family decided to continue only with palliative care.

Six months later, the patient returned to the emergency department due to extreme fatigue and poor oral intake; assessments showed she was suffering from severe electrolyte derangements, with severe hyponatremia and severe hyperkalemia (sodium level 118 mEq/L, potassium level 7.1 mEq/L). She was admitted and received medical and supportive management, but ultimately died of respiratory failure.

Discussion

Discussing this case of MiNEN – i.e., a combination of both adenocarcinoma and neuroendocrine carcinoma – Al Buthi and co-authors said that in the context of underlying chronic inflammatory disease, this rare aggressive subtype of neuroendocrine neoplasms involving the colon accounts for just 1.16 cases per 1,000,000 individuals.

Regarding the larger picture, the case authors noted that patients with UC have a greater risk of developing colorectal cancer (CRC) than the general population, with an overall risk of 1.29 cases per 1,000 IBD patients.

Of all CRCs, very rarely occur in the colon, accounting for less than 1% of CRCs, and even fewer IBD patients, the authors wrote, noting that only 16 cases have been reported in the literature. As well, NENs associated with UC affect twice as many males as females. This case is one of only four reports of coexisting IBD and MiNEN, making the current case even more unusual.

NEN is known to have a poor , in part because it frequently metastasizes -- to the liver in more than half of reported cases, the authors explained, adding that overall, reported 1-year survival rates are 40%.

Characteristics

MiNEN is defined as the presence of >30% of adenocarcinomatous component of the tumor masses, characterized by strong staining for synaptophysin and positive Ki67 marker in more than 70% of cases, including this case, Al Buthi and co-authors said.

Of the other three reported MINEN cases, two involved the rectum and one the sigmoid colon, while in this particular patient's case, the case authors said, a transverse colon MiNEN was found with two other masses in the descending colon.

are identifiable as a discrete component with at least 30% of the neoplasm morphologically and immunohistochemically recognizable, the authors noted. "Most epithelial neoplasms in the GI tract are subdivided into either pure glandular or squamous neoplasms (or their precursors) or pure neuroendocrine neoplasms."

Histopathological analysis of glandular and squamous neoplasms may identify a few interspersed neuroendocrine cells -- "but this finding does not affect the classification," the group said, noting that in fact, in rare instances, epithelial neoplasms may include significant populations of neuroendocrine and non-neuroendocrine cells.

Previously, mixed neoplasms in which each component accounted for 30% or more of the neoplasm were categorized among mixed adenoneuroendocrine carcinoma. The new term of mixed neuroendocrine/non-neuroendocrine neoplasm is used since the neuroendocrine component may not be adenocarcinoma, and to reflect the possibility that one or both components may not be carcinoma, Al Burhi and co-authors explained

According to the 2019 of tumors of the digestive system, "MiNEN is regarded as a conceptual category of neoplasms rather than a specific diagnosis," since various types of MiNENs can develop in different locations throughout the gastroenteropancreatic system.

Management Recommendations

Al Buthi and co-authors noted that while little is known about the prognosis, and an approach to treatment remains to be defined, they advised surgery for resectable intermediate-grade MiNEN as well as chemotherapy targeting both tumor components when a distant metastasis is detected.

"High-grade MiNEN is the most commonly seen, as in our patient, and is considered the most aggressive type," the group wrote. for MiNENs include surgery and adjuvant chemotherapy for localized lesions that have not metastasized, and systemic chemotherapy for distant metastasis. The team also cited the latest , which state that MiNENs of the GI tract are associated with a poor prognosis and should be managed as advised by the adenocarcinoma of the colon and rectum guidelines.

"After encountering this case and reviewing the literature, a clear association was identified and specific characteristics were found between MiNENs and UC," the case authors concluded. "As it is considered rare, this would represent distinct disease features that require further evaluation. Further research studies with larger sample sizes would help to understand the pathogenesis, diagnosis, management, and prognosis."

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