MINEN

初期像はSMTである、という報告

(1)「NET G2 と腺癌が混在した直腸MiNENの 1 例」より


SMTに見える早期MINEN


(2)

中島の報告した早期MiNENもSMT様に見える
NETG1と記載されている


(3)ESD後に消化管NETG1と腺癌の併存病変と診断した直腸粘膜下腫瘍の1例
症例は67歳男性.大腸内視鏡検査で直腸に5〜6mmの粘膜下腫瘍を認め,1年後の再検査で9〜10mmに増大傾向を示した.神経内分泌腫瘍(neuroendocrine tumor;NET)の疑いで,内視鏡的粘膜下層剥離術(endoscopic submucosal dissection;ESD)を施行し,NETG1と高分化型腺癌の併存病変という非常にまれな腫瘍の診断に至った

(4)経過観察中の20ミリの直腸SMT(カルチノイド)の頂部に腺癌が発生した例

日本消化器病学会編集によるオフィシャルなガイドライン

しかし、よく読むと・・・・こんなことは、WHO分類には、どこにも書いていない(文献
「NETはMEN,DAX,ATRX異常が見つかる」「NECはP53とRB異常」だから「全くの別物」
「MINENは腺癌やNECに似ており、NETとは別物」であり腫瘍進化だろうという話

Shiaの論文にも、腺腫⇒MINENの話は、全く記載がない。多分、下記のMESIERの論文と間違えたのだろう

MESIERの2017年の仮説

 Such event can occur at various stages, including early stages such as adenoma, since cases of MiNEN combining PDNEC and adenoma, without adenocarcinoma, have been reportedとして以下の二つの文献が紹介されているが、「PDNEC and adenoma」の例は「極めて稀」と一般的とは言えない

 66 Li Y, Yau A, Schaeffer D, Magliocco A, Gui X, Urbanski S, et al: Colorectal glandular-neuroendocrine mixed tumor: pathologic spectrum and clinical implications. Am J Surg Pathol 2011;35:413-425
右側に多い。ポリポイド型も多い。腺腫⇒腺癌⇒NECという仮説を主張

71 Vortmeyer AO, Lubensky IA, Merino MJ, Wang CY, Pham T, Furth EE, et al: Concordance of genetic alterations in poorly differentiated colorectal neuroendocrine carcinomas and associated adenocarcinomas. J Natl Cancer Inst 1997;89:1448-1453.PDNC and associated adenocarcinoma appear to be derived from the same cell of origin, which is most likely either a pluripotent epithelial stem cell or an adenocarcinoma precursor cell.


MINENのPDNEC成分はInvasive Adenocarcinomaと比較して、以下の遺伝子変異が追加されているという報告が根拠だが・・・・・CDKN2A以外は根拠が怪しい
CDKN2A, PAX6(クロマチン修飾), SMARCA4(クロマチン修飾), or INT2 genes, those encoding for proteins of the APC/β-catenin pathway, or those involved in the AKT/mTOR pathway. 

<重要>Low Grade MiNEN(PDNECではなくてG1,G2のような分化型)では遺伝子変化は腺腫型では無くて、通常のカルチノイドと同じパターンが多い。この現象からは「共通起源」の方が合う
well-differentiated NET components of MiNEN do not harbour similar genetic alterations described in the adenoma/adenocarcinoma counterpart, such as LOH of APC, KRAS, and TP53, but display specific alterations that are usually found in NET (but not PDNEC), such as LOH of VHL

     CDK2NA  APC    
膵臓   腺癌  28%  2%    
 PDMEC  27%  3%    
大腸   腺癌  9%  50%    
 PDNEC  6%  47%    

MINENの遺伝子変化は「発生臓器の腺癌に似る」出典

更に「Besides, radiotherapy and chemotherapy might favour genomic instability and transdifferentiation towards the PDNEC component, based on observations that the number of neuroendocrine markers-positive cells increased following neo-adjuvant treatments [18,65]. This strongly suggests that the PDNEC component develops during a classic adenoma-adenocarcinoma sequence. 」と言うが全く意味不明


MANETの論文


胃のMANET(2020年の報告)
Neuroendocrine component is generally located within the deep central portion of the polyp, whereas the adenomatous component occupies most of the periphery
Endoscopic macroscopic findings included sessile polyps in 5 cases, 0-IIa type polyp

Low-grade neuroendocrine tumors arising in intestinal adenomas: evidence for alterations in the adenomatous polyposis coli/β-catenin pathway

2020年の最新レヴュー
MEEN Mixed epithelial endocrine neoplasms of the colon and rectum

enteroendocrine cells are derived from common precursor gastrointestinal stem cells within the intestinal crypts and do not originate from the neural crest cells
non-neuroendocrine elements in MiNENs are always epithelial (glandular, squamous, mucinous and/or sarcomatoid) and do not include non-epithelial components such as lymphomas[3-9] or mesenchymal components such as smooth muscle tumors

mixed adenoneuroendocrine carcinoma of the pancreas suggests NEC as the precursor giving rise to the adenocarcinoma component, with both of them diverging from a single cancer stem cell

MANEC is a microsatellite stable tumor with strong positivity to CD44 and no expression of maspin suggesting an origin from a CD44-positive stem like precursor cell

In depth mutational analyses by Woischke et al[56] supports the concept of early separation of epithelial and neuroendocrine components during malignant transformation followed by subsequent independent mutational evolution

PDNEC of various origins showed cyclin-dependent kinase Inhibitor 2A/B and APC mutations.

The pathway leading to MSI high NEC/MANECs is the widespread methylation induced silencing of the MLH1 gene as seen in sporadic colorectal carcinomas.

The lack of mutations in ATRX, DAXX, MEN1, and TSC2 also supports a distinctive molecular evolution for the NEC component in comparison to NET tumors

intermediate to high grade colorectal MiNENs exhibit a genetic/molecular profile of identical copy number aberrations, similar to pure colorectal adenocarcinomas though they lack structural chromosomal alterations seen in pure colorectal NEC

Approximately, 5% of colorectal MiNEN are low grade mixed tumors, presenting as polyps < 3 cm in diameter and being composed of tubulovillous or villous adenoma with G1-G2 NET

no alterations are seen of KRAS, BRAF and Pik3CA genes in either tumor component of colonic MANETS.

Another area of continued debate is the WHO discriminatory criterion cut off 30% rule for each component for inclusion as a mixed tumor. . We strongly recommend that there should be continued reporting of any second component especially with poorly differentiated histology or evidence of invasion, regardless of its percentage volume.

The reasons underlying the presence of only one component in the most distant metastases need to be explored

limited biopsy material as in upto one third of the cases only one of the tumor components is identified


実は純粋なNECは存在しない、と予想されている
It is postulated that most pure endocrine cell carcinomas of colon and rectum if examined thoroughly will be associated with a carcinomatous element

somatostatin receptors scintigraphy for the diagnosis and follow-up of MANECs

進行した腺癌や内分泌癌を詳細に調べると、高率に「異なる分化した癌の成分」が見つかる、これらでは脱分化が起きていると思われる。そういう意味では30%ルールを無くせば「全ての大腸癌はMiNENである」という話になる。実際に「大腸癌の30%はMiNENである」という意見もある

「腺癌⇒内分泌癌へ脱分化」と「内分泌癌⇒腺癌へ脱分化」では、前者の方が圧倒的に頻度が多いのだから、進行したMiNENの多くは「腺癌⇒内分泌癌へ脱分化」と思われる。これで(1)内分泌癌の遺伝子異常はNETよりも腺癌に近い(2)内分泌癌の遺伝子異常は腺癌の遺伝子異常プラスアルファ(最も重要なのはCDKN2A)(3)形態的にBorT〜U、であることが説明できる

前立腺癌にはNeuroEndocrine Cell-Differentiationという現象が良く起こるらしい

一方、(1)早期のMiNENが粘膜下腫瘍様である(2)内分泌癌は以前はNETG3として認識されており粘膜下腫瘍と認識されていたもではないか?(3)MANETでは表層を腺腫、深部にNETが配置されている(4)GCC(Goblet Cell Cartinoid)というamphicrine tumorが、見つかる
・・・・・・・という現象からは「両分化能を持つ幹細胞に近い細胞が腫瘍化した」というモデルが支持される

上行結腸のTsp型 MinENの報告



High grade evolution of a MANETモデル
primary high grade NEC rarely occurs in patients with FAP in contrast to neuroendocrine hyperplasia and well differentiated NET supporting the theory that the evolution of NEC is distinct from NET in these mixed tumors


東大(渡辺教授)が2017年に出したMANECの論文
MiNENと通常の大腸癌はCFでは、区別できない。NETのようにSMTの形態をとらない。MANECのほとんどはBorrmanTかUである


Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas 2017年論文

Our data indicate that colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas, suggesting that the cells giving rise to these tumors primarily have an intestinal coinag
Point mutations in neuroendocrine neoplasm-related genes like RB1 or RET were not detected
RET=内分泌腫瘍、甲状腺癌で陽性。MENのようなもの

RETとRB1がカルチノイド(NET)のマーカーになり。しかしNECでは、これらの異常は無い


Amphicrine carcinoma という概念

Previous studies had demonstrated the excellent performance of the 90-gene expression signature for identification of tumor origin [, ]. After hierarchical clustering of the gene expression magnitudes, the pan-cancer panel reflected the similarity between the mRNA expression profile in amphicrine carcinoma and traditional adenocarcinoma, with no relationship between the amphicrine carcinoma and NET profiles. 

90-Gene Expression Profiling for Tissue Origin Diagnosis of Cancer of Unknown Primary


GCCについて


虫垂のAmphicrine tumors=「杯細胞カルチノイド(GCC)と粘液癌の両性質癌」
の報告 2014年
GCCは主に虫垂に見つかる。外分泌と内分泌の両方の性質を持つ。「虫垂のMINEN」。多分化能幹細胞から発生するという仮説を「unitary intestinal stem cell theory」と呼ぶ(Unitarian Theory of the origin of the four epithelial cell types.と同じ考え)。GCCは粘液癌、MINEN,印鑑細胞癌と深い関係があるはずである。

2018年 GCCは予後が悪い。また粘液産生から急性虫垂炎を起こし易い

2021 appendiceal neuroendocrine tumors (ANETs) low-grade appendiceal mucinous neoplasm (LAMN)  の合併