REV ARGENT COLOPROCT | 2024 | VOL. 35, N

2 CASE REPORT

MiNEN OF THE COLON: UNIFYING CONCEPTS Pérez Domínguez RS, et al.

Neuroendocrine-non-neuroendocrine neoplasia of the colon

(MiNEN): Unifying concepts

Rocío S. Pérez Domínguez MAAC, Guillermina Candia, Rosario O. Martiarena, Sergio F. Schlain MAAC

Hospital Interzonal General de Agudos San Roque, Gonnet

ABSTRACT

Neuroendocrine tumors represent 1% of all malignant neoplasms of

the digestive system, of which 14-20% correspond to the colon and

only 1-3% to the rectum. Eighty-five percent of colon neoplasms

are poorly differentiated neuroendocrine carcinomas that contain a

non-neuroendocrine component in 25-40% of cases.

An unusual clinical case with difficult preoperative diagnosis, in a

71-year-old female patient is presented. She consulted due to

change in bowel habits and abdominal pain in the left lower quad-

rant. CT scan reported a 10 cm solid mass in the rectosigmoid

colon, with multiple liver lesions compatible with metastases. Left

hemicolectomy with left salpingo-oophorectomy was performed. A

brief summary of the different names and classifications of this

entity that have occurred in recent years is presented.

Keywords: MiNEN, adenoneuroendocrine carcinoma, colorectal

neoplasia.

INTRODUCTION

The coexistence of neuroendocrine (NE) and non-

neuroendocrine (NNE) components in the same neoplasm,

or mixed NE and NNE neoplasm (MiNEN), is a well-known

but rare phenomenon. Cordier in 1924, first described the

gastrointestinal tumors containing epithelial and NE compo-

nents. Various terms have subsequently been used to de-

scribe this hybrid tumor.

Due to its dual histopathological

features, the clinical behavior of MiNEN differs from that of

NE carcinoma and classic adenocarcinoma.

NE neoplasms represent 1% of all malignant neoplasms of

the digestive system. According to a multicenter study by

the Japanese Colon and Rectal Cancer Society that analyzed

the distribution of digestive NE neoplasms, of a total of 760

patients, only 1.3% corresponded to MiNEN.

NE neoplasms of the colon represent 14 to 20%, while those

of the rectum only 1 to 3%.

Most NE neoplasms of the

colon (85%) are poorly differentiated and contain a NNE

component in 25-40% of cases, which can be an adenocar-

cinoma (45-65%), an adenoma (30-35%) or a squamous cell

carcinoma (5%). The NNE component arises from the

mucosa, while the NE component develops from a deeper

layer, which may be missed when a deep biopsy or radical

resection is not performed.

We present a rare clinical case with difficult preoperative

diagnosis, along with a brief summary of the different

names and classifications of this entity that have been

presented in recent years.

CASE

A 71-year-old female patient, with a history of hypertension

and appendectomy, consulted due to a change in bowel

habits, associated with pain in the left lower quadrant that

was relieved with defecation. On physical examination, she

had a soft abdomen, painful on deep palpation in the flank

and left iliac fossa, where a voluminous, hard stone mass

was evident, which appeared adhered to deep planes, meas-

uring approximately 7 x 5 cm. The proctological examina-

tion was normal.

Ca 19-9: 2.36 U/ml; CEA: 2.5ng/ml. Three colonoscopies

were performed, all of which showed a punctate stricture in

the sigmoid colon that prevented progression of the endo-

scope. The biopsy showed colonic mucosa with atypical

cells, without a specific histological diagnosis.

Abdominopelvic CT scan showed a 1.4 cm nodule at the

base of the right lung and focal hypodense hepatic lesions

with heterogeneous enhancement, the largest (8 cm) in the

right liver lobe, consistent with metastasis. In the left iliac

fossa, an irregular solid mass measuring approximately 10

cm was observed, compatible with an atypical lesion of the

entire colon wall (Fig, 1). Enlarged lymph nodes were seen

in the retroperitoneum, with the largest conglomerate (3.8

cm) in the left prerenal paravertebral region.

Given the progressive occlusive symptoms and the absence

of a definitive histological diagnosis, surgery is indicated.

The laparotomy revealed little free serous fluid and a volu-

minous mass in the sigmoid colon measuring 15x10 cm,

attached to deep planes. Multiple metastases in both liver

lobes, the largest measuring 12 cm. An en bloc left hemi-

colectomy with left salpingo-oophorectomy was performed

Histopathological examination informed a mixed NE and

NNE neoplasia (small cell NE carcinoma with moderately

differentiated adenocarcinoma) is observed invading adja-

cent structures (left Fallopian tube and ovary), with perineu-

ral and vascular invasion. Margins are free. Two of 12

lymph nodes have massive neoplastic infiltration. IHC:

chromogranin and synaptophysin positive in NE component.

CK20: positive in adenocarcinoma component. MiNEN,

pT4b pN1b M1 (Fig. 2).

Figure 1. Computed tomography. A. Large hypodense lesion involving the right and left hepatic lobes. B. Thickening of the sigmoid colon.

The authors declare no conflicts of interest. Rocío S. Pérez Domínguez: rocioperez@hotmail.com

Rocio S. Perez Dominguez: ORCID 0001-8347-0849, Guillermina Candia: ORCID 0003-2515-8923, Rosario O. Martiarena: ORCID 0001-8347-0849,

Sergio F. Schlain: ORCID 0002-5615-3503

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MiNEN OF THE COLON: UNIFYING CONCEPTS Pérez Domínguez RS, et al.

Figure 2. Histopathology. H&E. A. NNE component: adenocarcinoma. Atypical epithelial proliferation arranged in glands with different degrees of

differentiation, some retain mucosecretion. B. MiNEN. Glandular structures and solid areas. C. NE component: approximation of solid nuclei, cells

with a moderate amount of cytoplasm, homogeneous nuclei with salt and pepper chromatin, with different degrees of differentiation. D. IHC. Positive

labeling for chromogranin, with arrangement in solid nests.

DISCUSSION

The nomenclature of mixed NE and NNE neoplasms has

undergone numerous successive modifications in the last 20

years.

These neoplasms contain two or more different histological

components, with at least one of them of NE origin that

compromises at least 30% of the tumor, given that lower

percentages do not influence tumor behavior.

The diagnosis is made with the histopathological study.

Once hematoxylin-eosin staining demonstrates the presence

of NE and epithelial components, confirmatory testing with

immunohistochemistry should be performed. At least two of

three NE markers (synaptophysin, chromogranin, and CD

56) are used.

Historical evolution of nomenclature

For NE component

NE neoplasms were called “carcinoid tumors” since their

first description in 1907 and remained so for at least a

century. Then, in 1994, when a different behavior was

observed between well-differentiated and poorly differenti-

ated tumors, the latter were called “small cell carcinomas”

leaving the term carcinoid for the well-differentiated ones.

In 2010, with the arrival of the Ki-67 index, the WHO

adopted a classification based on this marker. Grade 1 and 2:

Ki-67 index ≤ 20% and Grade 3: Ki67 index >20%.

Fur-

thermore, according to their morphology, these tumors were

divided into well-differentiated or NET (NE tumor) and

poorly differentiated or NEC (NE carcinoma). Any of these

neoplasms, whether NET or NEC, can constitute the NE

component of a MiNEN.

For non-NE components

In 1987, Lewin formally proposed a classification system

for mixed NE neoplasms that he termed “composite glandu-

lar endocrine cell carcinomas”.

In 2000, these neoplasms were adopted in the WHO Classi-

fication of Tumors of the Digestive System as “mixed

exocrine-endocrine carcinomas” (MEEC), a terminology

that was short-lived and was modified by “mixed adenoneu-

roendocrine carcinoma” (MANEC) in a later edition (2010).

The goal was to create a comprehensive and appropriate

term for mixed NE neoplasms that could be used in any

organ, a difficult task due to the great variability of NE

neoplasms and their different sites of origin. The term

neoplasia or neoplasms, instead of carcinoma, was used to

be able to include the benign NNE component and remain

part of the MiNEN classification.

The diagnosis of these rare tumors is often challenging

because commonly only one component is identified. This

leads to incomplete diagnosis with suboptimal treatment. Its

management is recommended in multidisciplinary rounds

with expert pathologists and oncologists or with special

interest in NE neoplasms, which allows determining the

prognosis and adapting the treatment to the most aggressive

component of the tumor.

CONCLUSION

MiNEN is not a diagnosis, it is a general term used for

mixed neuroendocrine neoplasms. The interdisciplinary

team must know and be updated regarding the nomenclature

so that everyone speaks the same language. The challenge

for pathologists is to clearly report all tumor components, so

that oncologists can risk stratify and appropriately plan the

management of these neoplasms.

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MiNEN OF THE COLON: UNIFYING CONCEPTS Pérez Domínguez RS, et al.

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