Colon

Neuroendocrine tumors

Mixed neuroendocrine nonneuroendocrine neoplasm


Editorial Board Member: Naziheh Assarzadegan, M.D.
Deputy Editor-in-Chief: Catherine E. Hagen, M.D.
Maria Kamal, M.D.
Lewis A. Hassell, M.D.

Last author update: 23 May 2022
Last staff update: 23 May 2022

Copyright: 2019-2022, PathologyOutlines.com, Inc.

PubMed Search: Mixed neuroendocrine nonneuroendocrine neoplasm

Maria Kamal, M.D.
Lewis A. Hassell, M.D.
Page views in 2021: 880
Page views in 2022 to date: 2,665
Cite this page: Kamal M, Hassell LA. Mixed neuroendocrine nonneuroendocrine neoplasm. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/colontumormxdnrndcrnnonnrndocrnnplsm.html. Accessed December 3rd, 2022.
Definition / general
  • Extremely rare and aggressive with a high grade neuroendocrine component (in the majority of cases)
  • Composed of neuroendocrine cells, nonneuroendocrine cells or amphicrine cells that show both neuroendocrine and nonneuroendocrine cell differentiation (Int J Surg Case Rep 2020;76:125)
Essential features
  • Mix of neuroendocrine and nonneuroendocrine components, each constituting at least 30% of the tumor; both components should be histologically and immunohistochemically proven
  • Biological behavior is predominantly driven by the endocrine component, which is mostly poorly differentiated (World J Gastroenterol 2020;26:5181)
  • Prognosis of mixed neuroendocrine nonneuroendocrine neoplasm (MiNEN) is intermediate between that of pure adenocarcinoma and pure poorly differentiated neuroendocrine carcinoma (Neuroendocrinology 2017;105:412)
  • When considering treatment, the more aggressive component of MiNEN should be considered first; MiNEN containing a well differentiated neuroendocrine tumor (NET) (grades 1 or 2) component and an adenocarcinoma component should be treated as adenocarcinoma (J Chin Med Assoc 2015;78:454)
Terminology
ICD coding
  • ICD-10:
    • C7A.1 - malignant poorly differentiated neuroendocrine tumors
    • C7A.029 - malignant carcinoid tumor of the large intestine
    • C7A.020 - malignant carcinoid tumor of the appendix
    • C7A.8 - other malignant neuroendocrine tumors
Epidemiology
Sites
Pathophysiology
  • 3 main hypotheses:
    • First hypothesis: 2 components (endocrine and nonendocrine) arise independently from distinct precursor cells and unite
    • Second hypothesis: 2 components originate from a common pluripotent stem cell that undergoes biphenotypic differentiation during tumorigenesis
    • Third hypothesis: 2 components arise from a common precursor but postulates that the neuroendocrine component develops from an originally nonneuroendocrine cell, via progressive accumulation of genetic aberrations (World J Gastroenterol 2019;25:5991)
Etiology
Diagrams / tables

Images hosted on other servers:

Treatment modalities in retrospective study

Clinical features
  • Mass lesion, gastrointestinal bleeding, bowel obstruction, intussusception or paraneoplastic syndromes, rarely carcinoid syndrome
Diagnosis
  • Discovered during colonoscopy, some are diagnosed on evaluation of distant metastasis
  • Imaging features are nonspecific and necessitate histopathologic confirmation
  • CT is helpful in identifying and staging the disease
Radiology description
Radiology images

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CT with colon tumor

CT: liver metastasis, intraperitoneal fluid

Prognostic factors
Case reports
Treatment
  • First consideration is the more aggressive component of MiNEN
  • MiNEN containing a well differentiated NET (grades 1 or 2) component and an adenocarcinoma component, should be treated as adenocarcinoma (J Chin Med Assoc 2015;78:454)
  • Surgery preferred for nearly all potentially curable cases
  • Chemotherapy and radiotherapy considered on case by case basis (World J Gastroenterol 2020;26:5181)
  • Antiprogrammed death 1 receptor monoclonal antibody (pembrolizumab) therapy is effective where 5 - 10% of tumor cells express the programmed cell death receptor ligand 1 (J Immunother 2019;42:274)
Clinical images

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Tumor causing intussusception

Colonoscopy

Gross description
  • Polypoid or ulcerated tumor with raised edges or large fungating mass (World J Gastroenterol 2020;26:5181)
  • Cut surface of the tumor often shows white tan, poorly circumscribed lesions with an infiltrating border
  • Focal necrosis and foci of hemorrhage may be seen
Gross images

Images hosted on other servers:

Multiple polypoid masses

Microscopic (histologic) description
  • 2 components include epithelial / nonneuroendocrine component (mostly adenocarcinoma; less commonly, squamous cell carcinoma, acinar cell carcinoma, adenoma and other tumors) and neuroendocrine component, each constituting at least 30% of the tumor
    • This cut off value only applies to resected specimens after histological examination of the entire neoplasm within the specimen
  • Previously, these mixed neoplasms were classified under the category of mixed adenoneuroendocrine carcinoma; however, it is now recognized that the nonneuroendocrine component is not necessarily adenocarcinoma and either one or both components may not be carcinomas
  • Both components should be histologically and immunohistochemically proven
  • Per WHO, evaluate and grade each histologic component separately
  • All neuroendocrine components are classified according to the WHO criteria based on mitotic and Ki67 index, into well differentiated neuroendocrine tumors (G1, G2 and G3) and poorly differentiated neuroendocrine carcinomas (small or large cell neuroendocrine tumors)
  • Neuroendocrine component is mostly high grade and demonstrate a high mitotic index
    • Small cell type: nested or diffuse proliferation of tumor cells with round to oval nuclei, finely dispersed chromatin, inconspicuous nucleoli and scant cytoplasm
    • Large cell type: cells with abundant cytoplasm, vesicular nuclei and prominent nucleoli (Endocr Pathol 2016;27:284)
    • Prominent oncocytic differentiation represented by large cells with marked eosinophilia, has also been reported in a mixed tumor of the transverse colon (Endocr Pathol 2013;24:54)
  • Amphicrine tumors are distinguished by a divergent immunophenotype in which both exocrine and neuroendocrine traits are expressed in the same cell (Cancer Cell Int 2019;19:310)
  • About 5% of colorectal MiNEN show low grade neoplasms, combining adenomas with G1 / G2 NET (Neuroendocrinology 2017;105:412)
  • Because of possible response to platinum based treatments, the presence of even a minor component of small cell neuroendocrine carcinoma (SCNEC) should be mentioned in the diagnosis
    • Presence of a focal (< 30%) neuroendocrine component does not change the diagnostic categorization but it may be mentioned in the report
Microscopic (histologic) images

Contributed by Lewis A. Hassell, M.D. and Catherine E. Hagen, M.D.
Mixed acinar cell neuroendocrine carcinoma

Mixed acinar cell neuroendocrine carcinoma

Acinar cell carcinoma component

Acinar cell carcinoma component

Neuroendocrine carcinoma component

Neuroendocrine carcinoma component

Mixed adenocarcinoma neuroendocrine carcinoma

Mixed adenocarcinoma neuroendocrine carcinoma

Small cell carcinoma

Small cell carcinoma

Adenocarcinoma

Adenocarcinoma


Chromogranin immunohistochemistry

Chromogranin IHC

Synaptophysin immunohistochemistry Synaptophysin

Synaptophysin IHC

Trypsin immunohistochemistry

Trypsin IHC

Virtual slides

Images hosted on other servers:

Multiple polypoid masses

Positive stains
Negative stains
Molecular / cytogenetics description
Videos

Mixed neuroendocrine and nonneuroendocrine carcinoma of the esophagus

Mixed neuroendocrine nonneuroendocrine neoplasms

Sample pathology report
  • Sigmoid colon, resection:
    • Mixed neuroendocrine nonneuroendocrine neoplasm with well differentiated adenocarcinoma (G1, 30%) and poorly differentiated small cell neuroendocrine carcinoma (70%)
    • See synoptic report for more details

      Brief synoptic report
      Tumor site Sigmoid colon
      Histologic type Mixed neuroendocrine nonneuroendocrine carcinoma
      Size 4.5 x 2.0 x 1.2 cm
      Depth of invasion Subserosal adipose tissue
      Lymphovascular invasion Present
      Perineural invasion Not identified
      Margins Uninvolved by invasive carcinoma, intramucosal
      adenocarcinoma, high grade dysplasia and adenoma
      Lymph nodes with metastatic tumor 2
      Lymph nodes examined 15
      Tumor deposits Not identified
      Distant metastasis Not applicable
      AJCC staging pT3 N1
Differential diagnosis
Board review style question #1


An 8 mm polypoid mass located in the sigmoid colon was resected. The microscopic examination revealed a biphasic tumor that was positive for epithelial and neuroendocrine markers, each component accounting for > 30% of the tumor (see images above: chromogranin, trypsin). Which statement is true regarding this lesion?

  1. It is a common colorectal neoplasm
  2. It is mostly an aggressive tumor
  3. More common in females
  4. Recognized as part of the multiple endocrine neoplasia type 1 group of tumors
  5. Treatment is determined by the predominant (volume wise) component
Board review style answer #1
B. It is mostly an aggressive tumor

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Reference: Mixed neuroendocrine nonneuroendocrine neoplasm
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