Pancreas
Neuroendocrine neoplasms
Poorly differentiated neuroendocrine carcinoma
Editorial Board Member: Wei Chen, M.D., Ph.D.
Deputy Editor-in-Chief: Catherine E. Hagen, M.D.
Last author update: 8 August 2022
Last staff update: 31 October 2023
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PubMed Search: Pancreas neuroendocrine carcinoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology / etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Grading | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Mastrosimini MG, Luchini C. Poorly differentiated neuroendocrine carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasneuroendocrinecarcinoma.html. Accessed April 18th, 2024.
Definition / general
- Poorly differentiated, high grade, malignant epithelial neoplasm with neuroendocrine differentiation
- Poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs) are divided into small cell type (SC PanNEC) and large cell type (LC PanNEC)
Essential features
- Poorly differentiated neuroendocrine carcinomas represent a distinct entity from well differentiated (G1, G2, G3) neuroendocrine tumors (Am J Surg Pathol 2012;36:173)
- By morphology, PanNECs can be divided into small cell or large cell subtypes
- At the immunohistochemical level, the expression of neuroendocrine markers can be partial or weak (chromogranin A expression can even be absent)
- Tumor necrosis and high grade cytology
- Ki67 proliferation index > 20% (usually uniform and > 60%) (Ann Oncol 2013;24:152)
- Mitotic rate of > 20 mitoses/2 mm2
Terminology
- Neuroendocrine carcinoma refers to poorly differentiated neuroendocrine neoplasms, high grade by definition
- Neuroendocrine tumor is now reserved for well differentiated neoplasms with typical pathologic features of neuroendocrine lineage, truly resembling their nonneoplastic counterpart (cells of pancreatic islet), regardless of grade
- The current WHO (2019) classification groups pancreatic neuroendocrine neoplasms as follows:
- Pancreatic neuroendocrine microtumor (< 5 mm); previously known as neuroendocrine microadenoma
- Well differentiated pancreatic neuroendocrine tumor (WD PanNETs), including nonfunctional PanNETs and functional PanNETs (with clinical evidence of hormone release, such as insulinoma, glucagonoma, gastrinoma, VIPoma)
- Poorly differentiated pancreatic neuroendocrine carcinomas (PD PanNECs), including SC PanNECs and LC PanNECs
- Mixed neuroendocrine nonneuroendocrine neoplasm (MiNEN)
- Mixed neoplasm with a neuroendocrine component combined with a nonneuroendocrine component (typically ductal adenocarcinoma or acinar cell carcinoma)
- Each component must account for ≥ 30% of the tumor cell population and both components should be morphologically recognizable
- Neuroendocrine component may be a tumor (less frequently) or a carcinoma (more frequently)
ICD coding
- ICD-O:
- 8246/3 - neuroendocrine carcinoma, NOS
- ICD-11:
- 2C10.1 & XH0U20 - neuroendocrine neoplasms of pancreas & neuroendocrine carcinoma, NOS
- XH9SY0 - small cell neuroendocrine carcinoma
- XH0NL5 - large cell neuroendocrine carcinoma
Epidemiology
- Rare (accounting for < 1% of all pancreatic tumors and no more than 2 - 3% of pancreatic neuroendocrine neoplasms)
- Mean patient age is 59 years (patients are usually aged 50 - 60 years but can occur in younger patients as well)
- M:F = 1.4:1
- Large cell variant is more commonly encountered (60%) (Am J Surg Pathol 2012;36:173)
Sites
- Pancreatic gland (head, neck, body, tail)
- Head of the pancreas is the most common site (Am J Surg Pathol 2012;36:173)
Pathophysiology / etiology
- Largely unknown
- Tobacco smoking
Diagrams / tables
Images hosted on other servers:
Survival curves for
well differentiated
tumors and
carcinomas
Clinical features
- Back pain, jaundice (for PanNECs of pancreatic head) or nonspecific abdominal symptoms, likewise pancreatic ductal adenocarcinomas
- Neoplastic syndromes secondary to ectopic hormone production, such as ACTH (rare)
- Vast majority (> 90%) of patients present with metastasis at the time of diagnosis (Am J Surg Pathol 2012;36:173)
Diagnosis
- CT scan, MRI and ultrasonography are the preferred imaging modality
- FDG PET scans present high standardized uptake value
- Somatostatin receptor scintigraphy (SSRS) is often negative (or focal avidity) due to lack of expression of SSTR2 and SSTR5 (Arch Pathol Lab Med 2020;144:816)
- Diagnosis is by cytology / fine needle biopsy or on surgical specimens (Am J Surg Pathol 2016;40:1192)
Laboratory
- Serum hormone activity (such as chromogranin A) is very unusual (Cancer 1973;31:1523)
- Serum carcinoma associated markers (e.g., CEA, CA19-9, CA125) levels may be elevated (Am J Surg Pathol 2016;40:1192)
Radiology description
- CT and MRI features: irregular margins and frequent presence of necrotic foci within tumor mass
Grading
- PanNECs are, by WHO definition high grade, based on Ki67 (MIB1) index > 20% and mitotic rate > 20 mitoses/2 mm2
- WD PanNETs are graded from G1 to G3; but G3 PanNETs represent a distinct entity from PanNECs (Endocr Pathol 2022;33:115, Pathologica 2021;113:28)
Prognostic factors
- Very poor prognosis, compared to WD PanNETs
- Metastatic spread is present in most patients at the time of diagnosis
- MiNEN including a NEC component show an aggressive behavior: in these tumors, the Ki67 index of the NEC component is the most important prognostic driver (Endocr Relat Cancer 2018;25:583)
- Even in cases amenable to surgical resection and treated with adjuvant platinum based therapy, the median survival time is very short (< 1 year) and < 25% of patients survive beyond 2 years (Am J Surg Pathol 2012;36:173)
Case reports
- 27 year old woman with ACTH secreting PanNEC causing Cushing syndrome with pelvic and bilateral ovarian metastases (Int J Clin Exp Pathol 2015;8:15396)
- 56 year old man presenting with pure, alpha fetoprotein producing PanNEC without another coexisting malignant component, such as adenocarcinoma or hepatoid carcinoma (BMC Gastroenterol 2015;15:16)
- 65 year old man with SC PanNEC with similar genetic alterations to invasive ductal adenocarcinoma (KRAS mutation, altered expressions of TP53 and SMAD4 / DPC4) (Clin J Gastroenterol 2016;9:261)
- 67 year old woman with cutaneous metastases of a PanNEC with CK20 positivity (G Ital Dermatol Venereol 2018;153:722)
Treatment
- Surgical resection
- Chemotherapy (no established protocol): platinum based regimen (Pancreas 2021;50:138)
Gross description
- Large neoplasms with infiltrative borders
- Brownish to whitish color, fleshy or hard consistency and typically with grossly visible necrotic areas (Endocr Pathol 2022;33:115, Pathologica 2021;113:28)
Gross images
Images hosted on other servers:
Small cell carcinoma
Frozen section description
- High grade and hypercellular neoplasm, with necrotic areas
- Diagnosis should be postponed to definitive examination after formalin fixation and also supported by ancillary methods (Endocr Pathol 2022;33:115, Pathologica 2021;113:28)
Microscopic (histologic) description
- Hypercellular neoplasm, with large and irregular nests, infiltrative growth pattern with randomly oriented large vascular structures and desmoplastic type fibrosis
- Necrosis with geographic pattern and comedo-like appearance
- High rate of cellular turnover (high mitotic rate and high apoptotic rate) (Front Oncol 2013;3:2)
- SC PanNEC: diffuse sheets of relatively small cells with round or elongated hyperchromatic nuclei, finely granular chromatin and lacking nucleoli; typical feature of nuclear molding (sharing with the pulmonary counterpart) (Front Oncol 2013;3:2)
- LC PanNEC: nesting / trabecular pattern, with round to polygonal medium to large sized cells, with amphiphilic cytoplasm and atypical nuclei with either coarse chromatin or conspicuous nucleoli; the nuclear to cytoplasmic (N/C) ratio of LCNECs is lower than that of SCNECs
Microscopic (histologic) images
Contributed by Claudio Luchini, M.D., Ph.D. and AFIP images
General morphological appearance
Tumor necrosis
Large cell PanNEC
Small cell PanNEC
Nodal metastasis of PanNEC
Synaptophysin positivity
Chromogranin A positivity
Typical p53 expression
Rb loss
Focal necrosis
Intense immunostaining for NSE
Solid diffuse pattern
Scattered somatostatin immunoreactive cells
Cytology description
- Scant cytoplasm, slightly granular and high N/C ratio
- SC PanNEC: small cells with large nuclei, nuclear molding, finely speckled and dark chromatin with inconspicuous nucleoli, prominent background degeneration and typical crush artifact with nuclear streaming (Am J Surg Pathol 2012;36:173)
- LC PanNEC: large undifferentiated cells with bizarre forms or syncytial aggregates, irregular overlapping nuclei with prominent nucleoli, vesicular chromatin and abundant cytoplasm (delicate, dense or granular) (Am J Surg Pathol 2012;36:173)
Cytology images
Images hosted on other servers:
Overlapping pancreatic cells
Positive stains
- Cytokeratins (CK8 / CK18, CK AE1 / AE3)
- Synaptophysin: usually positive, may be rarely weak or focal (Am J Surg Pathol 2012;36:173)
- Chromogranin A: usually positive or weakly positive; can be also almost absent; SC PanNEC can also show a paranuclear dot-like immunoreactivity (Endocr Pathol 2018;29:150)
- CD56, neuron specific enolase (NSE), protein gene product 9.5 (PGP9.5) / ubiquitin C terminal hydrolase 1 protein (UCHL1): general neuroendocrine markers, less specific, limited utility
- Insulinoma associated protein 1 (INSM1) has emerged as an additional general neuroendocrine marker (Am J Clin Pathol 2015;144:579)
- Achaete-scute homolog 1 (ASH1) (Hum Pathol 2013;44:1391)
- p53: abnormal expression pattern / nuclear accumulation (Pathologica 2021;113:28)
- Useful (but neither ideal nor absolute) panel for determining pancreatic origin is PDX1+, ISL1+, PAX8+, CDX2+, TTF1- (Pathologica 2021;113:28)
Negative stains
- Rb (classic loss of Rb protein) (Am J Surg Pathol 2012;36:173)
- SMAD4 (Am J Surg Pathol 2016;40:1192)
- BCL10 (helping in excluding an acinar cell carcinoma or the presence of a focal acinar differentiation)
- Beta catenin (no nuclear staining; normal positivity of cell membrane)
Molecular / cytogenetics description
- Alterations of TP53 and Rb represent the most typical molecular events in PanNEC (Cancer Treat Rev 2017;56:28, Cancer Discov 2022;12:692)
- KRAS is also mutated in a significant proportion of cases (up to 30%) (Am J Surg Pathol 2012;36:173)
- Inactivation of SMAD4 / DPC4 is also reported (5%) (Am J Surg Pathol 2012;36:173)
- Microsatellite instability can be present in up to 5 - 8% of cases and should be assessed at the time of diagnosis (Hum Pathol 2022 Jun 14 [Epub ahead of print])
Sample pathology report
- Duodenum and pancreatic head, pancreaticoduodenectomy:
- Pancreatic neuroendocrine carcinoma, large cell type (see comment)
- Pancreatic head with the presence of a high grade neuroendocrine neoplasm
- Ki67 (MIB1) index 70%; mitotic rate: 50 mitoses/2 mm2
- Presence of tumor necrosis
- The neoplasm infiltrates distal choledochus, adipose tissue and duodenum
- Metastasis in 3/12 lymph nodes
- Surgical margins without tumor involvement
- Comment: The integration of morphology with the immunohistochemical profile (and in particular, CK AE1 / AE3 and CK8 / CK18 positive, synaptophysin positive, chromogranin A weakly positive, TP53: aberrant pattern; Rb: negative) is consistent with the diagnosis of pancreatic neuroendocrine carcinoma.
Differential diagnosis
- Well differentiated G3 neuroendocrine tumor (WD PanNET):
- Nonfunctional PanNETs are identified incidentally and have no symptoms
- PanNETs G3 show avidity on SSRS imaging (Octreoscan and Gallium 68 Dotatate PET / CT)
- Cytology: PanNETs G3 show abundant granular cytoplasm, low N/C and stippled chromatin
- Resection specimens: in PanNETs G3, the G3 component is usually not homogenous and mixed with a lower grade counterpart and the same for Ki67, which is heterogeneous
- Positive stains: in PanNETs, there are diffuse and strong chromogranin A (more specific) and synaptophysin (more sensitive) staining
- Molecular profile: in PanNETs, TP53 and Rb are usually wild type; there are recurrent and mutually exclusive mutations of DAXX (death domain associated protein, 25%) and ATRX (alpha thalassemia / intellectual disability syndrome X linked, 17.6%), usually wild type in PanNECs (Science 2011;331:1199)
- High grade neuroendocrine carcinomas of other sites (pancreatic metastasis):
- Other pancreatic primaries:
- Acinar cell carcinoma:
- Mixed neuroendocrine nonneuroendocrine neoplasms:
- Different components should be identified by morphology and not only by immunohistochemistry
- Medullary carcinoma:
- Syncytial growth pattern, intratumor inflammatory cells
- Negative for neuroendocrine markers
- Lymphoma:
- Melanoma:
- Small blue cell tumors in young adults:
- Desmoplastic small cell tumor (Am J Surg Pathol 2004;28:808):
- Large nests and broad bands of small blue cells, separated by fibrous stroma
- Positive stains: cytokeratins (AE1 / AE3 and CAM5.2), NSE, desmin and WT1
- Negative stains: chromogranin A, S100 and CD99
- Primitive neuroectodermal tumors (Am J Surg Pathol 2002;26:1040):
- Sheets and lobules of small cells with round to oval nuclei, nuclear molding and scant cytoplasm; no Homer-Wright rosettes
- Positive stains: CD99, cytokeratins (AE1 / AE3 and CAM5.2), NSE, chromogranin A or synaptophysin (may be focal or diffuse)
- Negative stans: desmin, actin, S100 protein, insulin, glucagon or somatostatin
- Desmoplastic small cell tumor (Am J Surg Pathol 2004;28:808):
Additional references
Board review style question #1
Which are the molecular hallmarks of PanNEC?
- CCND1 amplification
- DAXX and ATRX mutation
- EGFR alteration
- KRAS mutation
- TP53 and Rb alteration
Board review style answer #1
E. TP53 and Rb alteration. Indeed, the most typical molecular events in PanNEC are TP53 and Rb alteration. Immunohistochemistry is a good surrogate of their molecular status and in PanNEC it generally shows an aberrant expression pattern (usually a hyperaccumulation) for p53 and Rb loss.
Comment Here
Reference: Neuroendocrine carcinoma
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Reference: Neuroendocrine carcinoma
Board review style question #2
This photograph shows a primary pancreatic neoplasm. Which of the following histological features, present in the picture above, support the diagnosis of PanNEC?
- Acinar-like appearance
- Focal tumor necrosis and nuclear features
- Glandular formation
- Perineural invasion
- Vascular invasion
Board review style answer #2
B. Focal tumor necrosis and nuclear features. Tumor necrosis is a very important morphological feature for supporting the diagnosis of PanNEC but the immunohistochemical confirmation of the neuroendocrine nature is also very important.
Comment Here
Reference: Neuroendocrine carcinoma
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Reference: Neuroendocrine carcinoma
