Mixed Adenoneuroendocrine Carcinoma in the Colon: A Case Report

Abstract

Tumors that have both neuroendocrine and exocrine components in the gastrointestinal system are rare. One of the rarest places in the gastrointestinal system is the colon. These tumors are called mixed adenoneuroendocrine carcinomas (MANEC). To diagnose MANEC, the neuroendocrine and exocrine components that make up the lesion must be present at least 30%. A 70-year-old female patient with complaints of abdominal distension, malnutrition, nausea, and vomiting was admitted to our clinic from another center. The patient underwent blood tests, whole abdominal tomography, and colonoscopy. Right hemicolectomy and retroperitoneal lymph node dissection were performed with the preliminary diagnosis of colon cancer. Histopathological diagnosis was MANEC, and tumor stage was T3N1M0. Adjuvant chemotherapy was applied. Although MANEC is rare, it is a difficult and complex cancer to diagnose due to its nonspecific features. Diagnosis is made with histopathological and immunohistochemical evaluation along with clinical suspicion. Treatment is surgery and adjuvant therapy.

1. Introduction

Colon adenocarcinomas are the most common malignancy of the gastrointestinal tract, and the frequency of cancer development according to their histological types is 2–3% in tubular adenoma, 6–8% in tubulovillous adenoma, and 29–70% in villous adenoma [1]. Colon adenocarcinomas are the most common cancer of the digestive system and more than 50% of them progress with metastasis. Ki-67: It is an antigen that responds to nuclear nonhistone protein expressed in G1, G2, M, and S proliferative phases, and there is generally a good correlation between mitotic number and Ki-67. It is associated with cell proliferation [2]. Mixed adenoneuroendocrine carcinoma (MANEC) includes neoplasms that contain both neuroendocrine carcinomatous and adenocarcinomatous components. Its morphology is similar to that of advanced adenocarcinoma and differs from neuroendocrine tumors (G1 or G2), which usually present as a submucosal tumor with or without delle [1, 2, 3].

The neuroendocrine system includes endocrine glands such as the pituitary, parathyroid, and neuroendocrine adrenal. Endocrine islet tissues are found scattered within the exocrine parenchyma, such as the digestive and respiratory systems, as well as within the thyroid and pancreas. The gastrointestinal tract is the region where neuroendocrine cells are commonly located and 2/3 of neuroendocrine tumors (NETs) are located [4]. Neuroendocrine tumors (NET) are a heterogeneous group of tumors originating from neuroendocrine cells. These cells are specialized cells that have the ability to produce, store and secrete peptides, and biogenic amines. The common feature of these tumors is that they express both neural and endocrine markers, so they are called gastroenteropancreatic neuroendocrine tumor (GEP-NET). NETs are divided into two main groups: well-differentiated neuroendocrine tumor and poorly differentiated neuroendocrine carcinoma. Well-differentiated neuroendocrine tumors are called carcinoid tumors. Neuroendocrine tumors have been described in the central nervous system, respiratory system, larynx, gastrointestinal (GI) tract, thyroid, skin, breast, and urogenital tract [3, 5].

According to the WHO 2010 classification of GEP-NETs (Table 1), it provides a grading and naming system based on the morphological characteristics of tumors and cell proliferation rates, according to the criteria put forward by the European Neuroendocrine Tumor Society (ENETS) [6]. The common feature of these tumors is that they express both neural and endocrine markers, so they are called gastroenteropancreatic neuroendocrine tumor.

WHO 1980	WHO 2000	WHO 2010	2019
Carcinoid	Well-differentiated neuroendocrine tumor Well-differentiated neuroendocrine carcinoma Poorly differentiated neuroendocrine carcinoma /small cell carcinoma	Neuroendocrine tumor (NET) G1 Neuroendocrine tumor (NET) G2 Neuroendocrine carcinoma (NEC) (large cell or small cell type)	Neuroendocrine tumor (NET) G1 Neuroendocrine tumor (NET) G2 Neuroendocrine tumor (NET) G3 Neuroendocrine carcinoma (NEC) G3 (large or small cell type)
Mucocarcinoid Carcinoid-adenocarcinoma mixed forms Pseudotumor lesions	Mixed exocrine-endocrine carcinoma	Mixed adenoneuroendocrine carcinoma (MANEC)	Mixed neuroendocrine non-carcinoid- (MANEK) neuroendocrine neoplasia (MINEN)
Pseudotumor lesions	Tumor-like lesions	Hyperplastic and preneoplastic lesions

Table 1.

Classification of neuroendocrine tumors in the gastrointestinal system [6, 7, 8].

In 2019, common classification criteria for all NETs were republished by WHO (Table 1). The main feature of this new classification is to distinguish well-differentiated neuroendocrine tumor, previously known as carcinoid tumor of the gastrointestinal tract, from poorly differentiated neuroendocrine carcinoma. In general, distinguishing between well-differentiated and slow-growing neuroendocrine neoplasms and poorly differentiated and fast-growing neuroendocrine neoplasms is of great clinical importance. The two main groups, which are primarily divided into poorly differentiated and well-differentiated neuroendocrine neoplasms according to histomorphologic features, actually differ from each other genetically, molecularly, biologically and morphologically except for neuroendocrine features. Neuroendocrine neoplasms are evaluated morphologically and grouped as neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC) according to the degree of differentiation into the cells from which they originate. This distinction is supported by genetic evidence, and it is known that tumors differ clinically and prognostically [5, 6, 7, 9, 10, 11, 12].

Although colon NETs are rare, rectal NETs constitute 20% of GEP-NETs. It is seen in 5–6 Decade, and the incidence is equal in men and women. Colon NETs are histologically poorly differentiated neuroendocrine carcinoma. Metastasis is usually present at the time of diagnosis. It has a severe prognosis. Abdominal pain and weight loss may occur. Carcinoid syndrome may develop in less than 5% of patients. Rectal NETs are more common and have a better prognosis than colonic ones [12, 13]. They are mostly asymptomatic, and carcinoid syndrome is not observed. Patients with symptoms usually present with rectal bleeding, pain, or constipation. Most are smaller than 1 cm. Metastases can be seen in tumors larger than 2 cm and with invasion of the muscularis propria. Poorly differentiated neuroendocrine carcinomas have a poor prognosis. All neuroendocrine carcinomas are high-grade carcinomas. They show neuroendocrine differentiation both morphologically and immunohistochemically. Morphologically, they are divided into two groups: small cell and large cell. In the small cell group, cells have fine granular chromatin, and narrow cytoplasm and show morphological features, such as nuclear molding. In the large cell group, the cells have a moderate amount of cytoplasm and a round nucleus, sometimes with prominent nucleoli. NECs are aggressive tumors with high proliferative activity. The Ki67 proliferation index of tumors in this group is 20% and above. Most of the time it is above 75%. It is possible to see the Ki67 proliferation index around 20–50%, especially in cases exposed to chemotherapy. This is one of the situations confirming that the Ki67 index should not be used to differentiate neuroendocrine carcinomas and G3 neuroendocrine tumors [12, 13, 14].

Neuroendocrine tumors are rare in the colon and rectum, accounting for less than 2.0% of all colorectal malignancies. In some cases, neuroendocrine carcinoma and adenocarcinoma may occur together in the same tumor. According to the current classification of the World Health Organization (WHO), tumors in which neuroendocrine carcinoma and adenocarcinoma coexist are called “mixed adenoneuroendocrine carcinomas” (MANEC) [15]. MANEC is a neoplasm characterized by significant histological heterogeneity. In diagnosis, both neuroendocrine and adenocarcinoma components must be present simultaneously in ≥30% of cases. Mixed adenoneuroendocrine carcinoma, newly included in the 2010 WHO classification, is a rare tumor of the gastrointestinal tract that contains at least 30% of both adenocarcinoma and neuroendocrine carcinoma components. A total of 87% originates from the appendix. It is a very rare tumor in the colon and other parts of the gastrointestinal tract [1, 6, 15].

MANEC can be seen in every part of the gastrointestinal tract. The most common sites for MANEC are the esophagus [16], stomach [17, 18], appendix [19], gallbladder [20, 21], and pancreas [22]. It is rarely seen outside these regions. Although rare, cases of MANEC have been reported in areas, such as the colon [23, 24, 25, 26, 27, 28] and duodenum [29]. The most common site of MANEC in the colon is the right colon (56%), followed by the left colon and transverse colon [27]. Colon NETs are usually EC cell NETs, while rectal NETs are usually L-cell NETs. Colon NETs form larger masses than NETs seen in other parts of the gastrointestinal tract. Rectal NETs are observed as small polyps or submucosal nodules. Most of these are in the G1 category [8, 27, 28, 29]. In this study, we present a rare case of MANEC that occurred in the ascending colon and was indistinguishable from adenocarcinoma.

2. Case report

A 70-year-old female patient with complaints of abdominal distension, malnutrition, nausea, and vomiting was admitted to our clinic from another center. Her clinical condition started 1 month ago and gradually worsened despite all conservative treatments. A mass was detected in the cecal region during the patient’s colonoscopy. No malignancy was found in the biopsies. In the entire abdominal tomography performed in our center, there was wall thickening starting from the cecum and extending to the ascending colon, but no other pathology was found. Colonoscopy was tried twice, but could not be reached distal to the mass. No abnormality was detected in the initial laboratory values. The patient underwent emergency laparotomy. There was a 2×3×2 cm mass, obstructing the lumen in the transverse colon. The patient underwent extended right hemicolectomy and retroperitoneal lymph node dissection (Figure 1).

Figure 1.

Right hemicolectomy material A: Tumor B: Colon C: Appendix D: Ileum.

In the pathological examination of the sample, it was determined that there was adenocarcinoma 60% classical acinar and mucinous pattern + neuroendocrine carcinoma and 40% large cell type (Figures 2 and 3).

Figure 2.

Adenocarcinoma.

Figure 3.

Neuroendocrine tumor.

The tumor invaded the subserosal fat tissue (T3). The tumor was grade 3 (poorly differentiated) ulcerovegetan. A total of 25 lymph nodes were evaluated. There was reactive hyperplasia in 23 nodes and signs of carcinoma metastasis in two nodes (N1). Since the neuroendocrine component constituted a large part of the tumor, the pathologist had no difficulty in seeing it. Tumor markers, such as CEA, CA125, and CA19-9, were at normal levels. Distal and proximal surgical margins appeared intact. Carcinoid syndrome was not observed in the patient. In immunohistochemical examination, there was diffuse staining with neuroendocrine component CD56 and synaptophysin (Figure 4). MLH6, MSH2, MSH6, and PMS were examined by immunohistochemical method and microsatellite instability was stable.

Figure 4.

Synaptophysin, immunohistochemical marker.

Ki-67 and synaptophysin are neuroendocrine-specific markers. They were also strongly stained in our patient [16, 27]. Ki-67 proliferation index was 80%. Histopathological stage was evaluated as T3N1bM0. Although Ki-67 was 80% and cisplatin (platinum) was suitable, treatment was started with etoposide because the general condition was poor, the ECOG performance score was two, and the creatinine level was at the border. Platinum-based treatment was not considered at the first stage. It was planned that platinum could be started depending on tolerance. The patient was given four cycles of etoposide. After the treatment was completed, the patient was evaluated with full abdominal CT and PET CT. During the period when this study was carried out on the case, the general condition of the patient tended to improve. No tumor deposits were found in control radiological examinations (abdomen CT, pet CT).

3. Discussion

MANEC is a rare tumor in the colorectal region. Therefore, studies on this tumor are limited. There are also a limited number of studies, although they are mostly in the form of case reports. Although the limited number of studies prevents us from drawing general conclusions regarding this tumor, the prognosis of these patients is worse than that of patients with routine colorectal cancer [30].

The definitive way to diagnose MANEC is through histopathological examination. How patients with MANEC will be treated, or how this disease will be managed has not been fully determined due to the rarity of these tumors. Treatment is usually directed at the more aggressive tumor component. Mixed adenoneuroendocrine carcinomas, containing a well-differentiated neuroendocrine tumor component and an adenocarcinoma component, should be treated as adenocarcinomas. Mixed adenoneuroendocrine carcinomas, containing a poorly differentiated neuroendocrine carcinoma component, should be considered as neuroendocrine carcinomas and treated accordingly [31]. The case we presented was also considered as neuroendocrine carcinoma and treated accordingly.

Some studies have shown that adjuvant chemotherapy is an effective treatment option for patients with MANEC [32]. However, it is not yet clear which chemotherapy regimen is most effective in treating patients with MANEC due to limited studies. Therefore, it is currently impossible to talk about the most effective chemotherapy regimen for patients with MANEC.

The clinical course of MANEC is neither similar to neuroendocrine carcinoma nor adenocarcinoma but different from both [33]. It is difficult to diagnose MANEC in these tumors without histopathological diagnosis. It does not have a specific clinical course or finding. Therefore, they are usually found by chance [2]. MANEC is usually diagnosed at an advanced stage, so its course is aggressive. Endoscopically, it appears as a semicircular or fungal tumor, covering the lumen with deep ulceration. However, due to their structural similarities, it is often difficult to differentiate from colorectal adenocarcinoma based on endoscopic appearance alone [33]. For this reason, like every colorectal tumor detected, histopathological examination and immunohistochemical staining are the most valuable diagnostic methods for MANEC, and for this, biopsy is required [2]. The National Comprehensive Cancer Network (NCCN) recommends CT and MRI with intravenous contrast for clinical staging. Contrast-enhanced thoracoabdominopelvic CT is recommended for distant metastasis screening [34]. Although the sensitivity of F-fluorodeoxyglucose positron emission tomography for detecting nodal involvement in neuroendocrine tumors is high, its sensitivity in colorectal adenocarcinoma and neuroendocrine tumors is considered low at 42.9% and 33%, respectively [33]. Colonoscopy and abdominal CT were performed for the diagnosis and staging of the patient we presented.

4. Conclusion

In conclusion, MANEC is a malignant tumor prone to distant metastases. Therefore, diagnosis is usually made in the late and metastatic stage. Although more is known about its clinicopathological features today, a consensus has not been reached regarding both its clinicopathological features and its treatment. Our patient’s clinical features and pathological features such as tumor localization, Ki-67, and tumor size were compatible with the literature. MANEC is a rare but highly aggressive disease. In this study, we aimed to present a rare colon MANEC patient to emphasize the term MANEC and to better understand the diagnosis, treatment, and management of MANEC. If the diagnosis is made in the early stages, surgical resection can be curative, but studies with a large number of patients are needed for the most appropriate treatment approach. More studies are needed to more clearly define how to manage patients with MANEC.