Pancreas

Other tumors

Mixed neuroendocrine nonneuroendocrine neoplasms (MiNENs)



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Last staff update: 7 April 2022

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PubMed Search: Mixed neuroendocrine non-neuroendocrine neoplasms pancreas

Jennifer Ziebell, M.D.
Ashwini Kumar Esnakula, M.D., M.S.
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Cite this page: Ziebell J, Esnakula AK. Mixed neuroendocrine nonneuroendocrine neoplasms (MiNENs). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasmixed.html. Accessed August 17th, 2022.
Definition / general
  • Pancreatic mixed neuroendocrine nonneuroendocrine neoplasms (MiNENs) are rare and heterogeneous malignancies characterized by histologically recognizable neuroendocrine (i.e., carcinoma and rarely, a well differentiated neuroendocrine tumor) and exocrine (usually ductal carcinoma, acinar carcinoma or both) components, each composing ≥ 30% of the neoplasm volume (Endocr Pathol 2016;27:284)
Essential features
  • Histologically recognizable neuroendocrine and nonneuroendocrine components each comprise ≥ 30% of the neoplasm
  • Neuroendocrine component is mostly a poorly differentiated neuroendocrine carcinoma (NEC); rarely a well differentiated neuroendocrine tumor (NET)
  • Exocrine component can either be pancreatic ductal adenocarcinoma (PDAC) or acinar cell carcinoma (ACC); very rarely, both acinar and ductal carcinoma
  • Neuroendocrine and nonneuroendocrine components are confirmed with immunohistochemistry (IHC)
  • Poor prognosis
Terminology
  • Subtypes: mixed ductal neuroendocrine carcinoma, mixed acinar neuroendocrine carcinoma, mixed acinar neuroendocrine ductal carcinoma
  • Not recommended: composite carcinoid, mucin producing carcinoid, argentaffin cell adenocarcinoma, goblet cell carcinoid, adenocarcinoid, small cell undifferentiated carcinoma (Cancers (Basel) 2012;4:11)
ICD coding
  • ICD-O: 8154/3 - mixed pancreatic endocrine and exocrine tumor, malignant
  • ICD-10:
    • C25.9 - malignant neoplasm of pancreas, unspecified
    • C7A.8 - other malignant neuroendocrine tumors
    • C25 - malignant neoplasm of pancreas
  • ICD-11: 2C10.0 & XH8E54 - mixed neuroendocrine nonneuroendocrine neoplasm (MiNEN)
Epidemiology
Sites
  • Anywhere in the pancreas
  • Mixed ductal neuroendocrine carcinomas are more common in the head of the pancreas
Pathophysiology
  • Unclear
  • May arise as the combination of 2 neoplastic clones or as the proliferation of 1 precursor cell with divergent differentiation; however, molecular and genetic studies point towards a monoclonal origin of both components (Endocr Pathol 2016;27:284, J Clin Med 2020;9:273)
  • Behavior is thought to be driven by the neuroendocrine component (J Clin Med 2020;9:273)
Etiology
  • Unknown
Clinical features
  • Presentation is nonspecific and depends on the tumor size and degree of metastatic disease
Diagnosis
  • Histomorphology and IHC on surgical resection specimens
  • Biopsy may be used but is vulnerable to limited sampling and inadequate quantification of tumor components (Int J Surg Pathol 2017;25:585)
Laboratory
Radiology description
  • Radiologic features of MiNENs can resemble either pancreatic adenocarcinoma or pancreatic neuroendocrine neoplasms on abdominal CT scan with contrast (Pancreatology 2021;21:224)
  • Imaging findings similar to pancreatic adenocarcinomas (including hypodense hypoenhancing mass with ill defined border) are commonly seen with mixed ductal neuroendocrine carcinomas
  • Imaging findings similar to pancreatic neuroendocrine neoplasms (including heterogeneously enhancing mass with or without cystic component and well defined margins) are commonly seen with mixed acinar neuroendocrine carcinomas
Radiology images

Images hosted on other servers:

MiNEN in the head of the pancreas on CT

MiNEN in pancreas head with portal vein narrowing on CT

Prognostic factors
  • Tumor size and resectability are the most important prognostic factors
  • Mixed ductal neuroendocrine carcinoma: 5 year survival rates are similar to PDAC and NEC
  • Mixed acinar neuroendocrine carcinoma: similar to 5 year survival rate (36 - 72%) of pure acinar cell carcinoma (Am J Surg Pathol 2012;36:1782)
  • A poorly differentiated neuroendocrine carcinoma component comprising > 50% of the tumor is associated with distant metastasis and poor prognosis (J Chin Med Assoc 2015;78:454)
Case reports
Treatment
  • No clear treatment guidelines due to rarity of tumors
  • Some recommend treatment based on the neuroendocrine component since it seems to be the most aggressive (Neuroendocrinology 2016;103:186, J Clin Med 2020;9:273)
    • Radical surgical resection with or without adjuvant chemotherapy for localized cases
    • Chemotherapy (platinum based) for extensively metastatic cases
Gross description
  • Mixed ductal neuroendocrine carcinomas are solid tumors with infiltrative margins similar to ductal adenocarcinomas
  • Mixed acinar neuroendocrine carcinomas are usually nodular, fleshy, hemorrhagic and necrotic, similar to neuroendocrine carcinoma and acinar cell carcinoma (Am J Surg Pathol 1994;18:765)
Gross images

Images hosted on other servers:

Mixed ductal neuroendocrine carcinoma

Microscopic (histologic) description
  • Neuroendocrine and nonneuroendocrine components are intimately intermixed and sometimes can only be differentiated with IHC (Int J Surg Pathol 2017;25:585)
  • Both components must comprise ≥ 30% of the neoplasm (Endocr Pathol 2016;27:284)
  • Neuroendocrine component can either be poorly differentiated neuroendocrine carcinoma or well differentiated neuroendocrine tumor (Surg Pathol Clin 2020;13:377)
    • Poorly differentiated neuroendocrine carcinoma (90% of MiNENs) (J Clin Med 2020;9:273):
      • Poorly formed trabeculae and nests or diffuse sheets of cells
      • Can be large cell types (moderate to abundant eosinophilic cytoplasm, fine to vesicular chromatin and prominent nucleoli) or small cell types (high nuclear to cytoplasmic ratio, hyperchromatic nuclei with fine chromatin, inconspicuous nucleoli)
      • Multiple foci of necrosis or geographic necrosis and numerous apoptotic bodies
      • Mitoses are frequent
      • Perineural and vascular invasion is common
    • Well differentiated neuroendocrine tumor:
      • Nested, lobular or trabecular architecture composed of monomorphic, regularly arranged cells
      • Nuclei with stippled (salt and pepper) chromatin
      • Inconspicuous nucleoli
  • Ductal adenocarcinoma component:
    • Identical to conventional pancreatic ductal adenocarcinoma
    • Grade ranges from well differentiated to poorly differentiated adenocarcinoma
    • Infiltrating, well to poorly formed glandular, cribriform, solid or trabecular structures surrounded by desmoplastic stroma
    • Mucin production
    • Perineural and vascular invasion are common
  • Acinar cell carcinoma component:
    • Identical to acinar cell carcinoma
    • Highly cellular
    • Cystic, acinar or glandular architecture
    • Abundant eosinophilic granular cytoplasm
    • Monomorphic nuclei with a single prominent nucleolus
    • Perineural and vascular invasion are common
Microscopic (histologic) images

Contributed by Jennifer Ziebell, M.D. and Ashwini Esnakula, M.D., M.S.
Mixed ductal neuroendocrine carcinoma Mixed ductal neuroendocrine carcinoma

Mixed ductal neuroendocrine carcinoma

Neuroendocrine carcinoma component

Neuroendocrine carcinoma component

Ductal adenocarcinoma component

Ductal adenocarcinoma component

Chromogranin A

Chromogranin A

 Ki67 neuroendocrine carcinoma component

Ki67 neuroendocrine carcinoma component

Cytology description
  • Diagnosis of MiNENs on FNA is exceedingly challenging due to cytomorphologic variability, sampling bias and the often minimal quantity of tissue available for cell block and (IHC (Diagn Cytopathol 2013;41:164, Acta Cytol 2013;57:296, Diagn Cytopathol 2018;46:971)
  • Mixed cytologic features of neuroendocrine and exocrine component (adenocarcinoma or acinar) should raise suspicion of MiNEN
  • IHC is helpful to demonstrate the endocrine and exocrine components
Positive stains
Negative stains
Electron microscopy description
  • Electron microscopy diagnostic findings (Am J Surg Pathol 1994;18:765, Pathol Int 2021;71:485):
    • Secretory zymogen granules in acinar cell component; usually > 500 nm in size
    • Neuroendocrine granules in neuroendocrine component; usually 100 - 200 nm in size
    • Mucinous granules in ductal adenocarcinoma component
Molecular / cytogenetics description
Videos

MiNEN basics

Sample pathology report
  • Pancreas tail and spleen, distal pancreatectomy:
    • Mixed neuroendocrine and nonneuroendocrine neoplasm (MiNEN) of pancreas composed of ductal adenocarcinoma and neuroendocrine carcinoma, 3.5 cm (see comment and synoptic report)
      • Tumor infiltrates the peripancreatic soft tissue
      • Prominent lymphovascular and perineural invasion is identified
      • Pancreatic parenchymal resection margin is negative for tumor
      • Metastatic neuroendocrine carcinoma is identified in 8 of 21 lymph nodes
      • Pathology stage: pT3 / N2
    • Spleen with no significant diagnostic alterations
    • Comment: The sections of the pancreatic tail mass show a biphasic appearance with histologically distinct ductal and neuroendocrine carcinoma components. The neuroendocrine component comprises approximately 60% of the tumor and is characterized by infiltrating sheets and nests of high grade tumor cells with moderate eosinophilic cytoplasm, vesicular chromatin and viably prominent nucleoli. Frequent mitoses are noted (up to 25/HPF). Areas of tumor necrosis are identified. A well differentiated ductal adenocarcinoma component, characterized by infiltrating well formed tubules, is seen intricately associated with the neuroendocrine carcinoma component. Neuroendocrine carcinoma shows diffuse and strong expression for neuroendocrine markers chromogranin and synaptophysin. The ductal carcinoma component is negative for neuroendocrine markers. Neuroendocrine carcinoma shows a Ki67 proliferative index of approximately 90%. Overall, the findings are consistent with mixed ductal neuroendocrine carcinoma of the pancreas.
Differential diagnosis
Board review style question #1

A 55 year old man presented with a 4 cm large pancreatic head mass. The sections from the resected tumor showed a mixed neoplasm with varied histologic findings, as highlighted in the image above. What is the most common component of such neoplasms?

  1. Acinar carcinoma
  2. Ductal adenocarcinoma
  3. Poorly differentiated neuroendocrine carcinoma
  4. Squamous cell carcinoma
  5. Well differentiated neuroendocrine tumor
Board review style answer #1
C. Poorly differentiated neuroendocrine carcinoma. The tumor is likely pancreatic mixed neuroendocrine nonneuroendocrine neoplasms (MiNENs) with ductal adenocarcinoma and poorly differentiated neuroendocrine carcinoma components. Poorly differentiated neuroendocrine carcinoma is the most common component seen in around 90% of MiNENs.

Comment Here

Reference: Mixed neuroendocrine nonneuroendocrine neoplasms pancreas (MiNENs)
Board review style question #2
In a mixed neuroendocrine nonneuroendocrine neoplasm (MiNEN), what is the lowest percentage of the neoplasm the neuroendocrine component can comprise in order to classify as a MiNEN?

  1. 20%
  2. 30%
  3. 40%
  4. 50%
  5. 60%
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