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A 57-year-old Saudi man presents to the emergency department noting that for the last 5 days he has had severe stomach pain, which has progressively intensified in the past few days.

He describes a painful feeling of bloating and pressure in his upper abdomen that persists regardless of his body position. In fact, he says that lying on his side makes the pain worse.

He is also wheezing and short of breath even when at rest. For the past few nights, he says he has had to sleep sitting up due to being short of breath when lying down. Other changes include a recent history of night sweats. His body mass index is 41, and he notes that since he started dieting a month ago, he has lost 4 kg (almost 9 lbs).

Clinicians taking the patient's history note that he has not had any loss of appetite, nausea or vomiting, or dark or bloody stools. Similarly, he has had no abdominal injury. He has not consumed alcohol or used illicit drugs, and there is no family history of gastrointestinal malignancies.

Physical examination finds the patient conscious and fully aware of his surroundings. Clinicians note marked abdominal distension and epigastric tenderness. He displays considerable pain and distress during the examination. There is no evidence of cervical lymphadenopathy. The abdomen was distended, with epigastric tenderness. Fluid wave test is positive; clinicians are not able to assess for organomegaly.

Vital signs are stable, as follows:

• Temperature: 37º C (oral)

• Respiratory rate: 20 breaths/minute

• Blood pressure: 116/72

• Peripheral capillary oxygen saturation: 98%

There is evidence of:

• Leukocytosis (32.500 × 10⁹/L): mainly neutrophils and monocytes

• Erythrocyte sedimentation rate elevation: 118 mm/hr

• C-reactive protein elevation: 173 mg/L

• Lactic acid slightly high: 2.1 mmol/L

• Hypoalbuminemia: 14.25 gm/L

Computerized tomography (CT) scan of the abdomen and pelvis reveals a large heterogeneously enhancing neoplastic mass lesion that involves the splenic flexure of the colon. It is surrounded by fat stranding, with a small contained leak just below the mass lesion; there is no evidence of bowel obstruction.

There is evidence of large loculated ascites in the abdomen, with scalloping of the liver surface, and several metastatic hypodense focal hepatic lesions. The scan also identifies numerous lymph nodes of less than 1 cm (Figure).

Treatment and Outcome

The patient is diagnosed with a bowel perforation. Surgeons perform an exploratory laparotomy subtotal colectomy and ileostomy creation and washout. Three drains are placed with closure en bloc.

Surgery involves excision of a 65-cm piece of colon and a peritoneal nodule, which are sent for histopathological analysis. The surgeons note that both surgical margins appear to be tumor-free away from both surgical margins.

Intraoperative findings include the following:

• Multiple pockets of pus (1.5 liters)

• Phlegmon involving the stomach and large bowel

• Multiple peritoneal neoplastic deposits

• Carcinomatosis of stomach, liver, and spleen

The patient is moved to the surgical intensive care unit, where he is intubated on inotropic support. He is treated with a regimen of meropenem and fluconazole to address culture findings showing heavy growth of Streptococcus anginosus and scant growth of Escherichia coli.

Surgical Findings

Histopathological examination of the splenic flexure mass reveals high-grade and invasive colonic neuroendocrine carcinoma (NEC) that is pT4 N2b M1c, while the peritoneal lesion is metastatic carcinoma.

The mitotic index is more than 20/10 high power fields with lymphovascular invasion, but perineural invasion cannot be determined. Ten tumor deposits are found in the pericolic fat, with metastases to nine of 10 lymph nodes.

Immunohistochemical staining reveals that the tumor cells are positive for synaptophysin, pan-cytokeratin, CD56, and CD117 -- associated with a poor prognosis. The proliferation marker (Ki-67) showed more than 90% positive nuclear staining.

Five days after surgery, the patient is showing progressive improvement. Vital signs are stable and he is able to eat and walk. He is moved to the general surgical ward for ongoing postoperative care.

Clinicians refer the patient to the multidisciplinary tumor board for proper assessment and management.

Discussion

Clinicians reporting ¹ of a man with a perforated colonic neuroendocrine tumor note that these rare tumors, found mainly in the gastrointestinal tract, account for only about 0.5% of all newly diagnosed cancers.²

These benign neoplasms, also known as neuroendocrine neoplasms (NENs) or carcinoid tumors, originate from cells of the endocrine and nervous systems, but with malignant neoplasms present.³

Colonic and rectal NENs account for 7.8% and 13.7%, respectively, of all neuroendocrine neoplasms. In recent decades, these neoplasms (especially of the large bowel) have been increasing in incidence and prevalence -- mostly due to advances in the classification and diagnostic approach.^4,5

As noted in a recent consensus ,⁶ neoplasms of the colon and rectum differ in that rectal NENs are usually small lesions (most less than 1 cm in size), and their histological malignancy is low to moderate -- i.e., Grade 1 or Grade 2. In contrast, those in the colon are often aggressive, poorly differentiated, and more malignant -- i.e., Grade 3.^6,7

As the case report authors note, colonic neuroendocrine tumors occur most commonly in females from ages 63 to 70, and often in the cecum area of the ascending colon. These cancers are generally diagnosed at a later stage -- and may present with signs of bowel obstruction, or be diagnosed as a result of a tumor being detected.^5,8

About 45% of cases are localized, while 16-40% are metastatic disease.^5,8 Malignant colonic tumors tend to have a more aggressive course, higher grade, and poor differentiation.^6,7

High-grade neuroendocrine tumors or carcinomas are malignant epithelial tumors; light microscopic, ultrastructural, or immunohistochemical evaluation reveals neuroendocrine differentiation.

These aggressive neoplasms -- which account for 0.1-3.9% of all colorectal malignancies -- have the lowest 5-year survival rate of all the neuroendocrine neoplasms of the gastrointestinal tract.⁹

Individuals with a family history of a neuroendocrine tumor in a first-degree relative are at a fourfold increased risk. Synchronous neoplasms account for 13% of cases.^4,5,8

About 75% of colorectal NECs develop in the ascending colon. In general, these typically begin as polyps, but by the time they are diagnosed, about 30% have metastasized to the lymph nodes, mesentery, peritoneum, and liver. These will be diagnosed as NECs or mixed neoplasms.^4,8

Less than 5% of neuroendocrine tumors are associated with specific or carcinoid syndrome symptoms, with most mimicking adenocarcinoma.⁴

Neuroendocrine tumors tend to be associated with diarrhea or other changes in bowel movements. More advanced cases may present with abdominal pain, weight loss, and signs of anemia due to gastrointestinal blood loss, and there may be palpable lesions in the abdominal cavity.^10,11

There is no diagnostic blood marker for colorectal NENs, although the case report authors note that assessment of serum chromogranin A concentration may be helpful.¹⁰ In this patient's case, clinicians reported that serum chromogranin A was not assessed due to the emergency nature of the case.

Treatment: Surgical and Chemotherapy Options

for colonic NENs include resampling of colonic adenocarcinoma. Patients with no evidence of distant metastasis should be treated with lymphadenectomy, while those with distant metastases (usually to the liver) could receive palliative regional lymphadenectomy or maximal cytoreduction of the tumor as a last resort.

In patients with metastasis to several organs, multi-organ excision including oncological resection of the involved colon is recommended.^8,12

Without chemotherapy, median survival is only about 1 month. Standard therapy for advanced NECs has been the platinum-with-etoposide regimen, due to morphological and biological similarities of these tumors to bronchogenic small cell carcinoma. However, further study is needed to fully validate this approach. Capecitabine, streptozotocin, fluorouracil, doxorubicin, and temozolomide may be considered as other options.^13,14

Patients with colonic tumors have a 5-year survival rate of 40-70%. Median survival times are 261 months for patients with locally advanced lesions, decreasing to 36 months for those with regional lymph node metastases, and 5 months for those with distant metastases.^4,5,8

Conclusions

Clinicians presenting this case note that the incidence of neuroendocrine tumors is progressively increasing, and cases often have an unusual presentation. Since colorectal NECs are rare, highly aggressive diseases (especially the colonic type), and are usually discovered very late in the disease course, individualization of management and additional research are needed.

References

1. Alshammari TF, et al: A perforated colonic neuroendocrine tumor with liver metastasis: A case report and literature review. Am J Case Rep 2019; 20: 920-925.

2. Larson MV: Gastric neoplasms and gastroenteric and pancreatic neuroendocrine tumors. Mayo Clinic Gastroenterology and Hepatology Board Review. 5th ed. New York: Oxford University Press, 2015; 65–66.

3. Ilett EE, et al: Neuroendocrine carcinomas of the gastroenteropancreatic system: A comprehensive review. Diagnostics (Basel) 2015; 5(2): 119–176.

4. Modlin IM, et al: A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97(4): 934–959.

5. Yao JC, et al: One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26(18): 3063–3072.

6. Ramage JK, et al: Vienna Consensus Conference participants. ENETS Consensus Guidelines Update for Colorectal Neuroendocrine Neoplasms. Neuroendocrinology 2016; 103: 139–143.

7. Amin MA ed, AJCC Cancer Staging Manual. 8th ed. New York, NY, Springer International Publishing, 2017.

8. Starzyńska T, et al: Consensus Conference, Polish Network of Neuroendocrine Tumours. Colorectal neuroendocrine neoplasms – management guidelines (recommended by the Polish Network of Neuroendocrine Tumours). Endokrynol Pol 2013; 64(6): 494–504.

9. Staren ED, et al: Neuroendocrine differentiation in 'poorly differentiated' colon carcinomas. Am Surg, 1990; 56: 412–419.

10. Kolby L, et al: Chromogranin A as a determinant of midgut carcinoid tumour volume. Regul Pept, 2004; 120(1–3): 269–273.

11. Davidson ED, McDougal WS: Elevated serum acid phosphatase levels with rectal carcinoid tumor. Gastroenterology 1976; 70(1): 114–116.

12. Sorbye H, et al: Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): The NORDIC NEC study. Ann Oncol 2013; 24: 152–160.

13. Hadoux J, et al: Postfirst-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma. Endocr Relat Cancer 2015; 22:289–298.

14. Moertel CG, et al: Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 1991; 68: 227–232.

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