By Anna C. Greene, PhD, NETRF Chief Scientific Officer
Patients often hear similar-sounding terms: neuroendocrine tumor, neuroendocrine carcinoma, NET, NEC, high-grade, poorly differentiated, well-differentiated. It can be confusing, especially when the words all include “neuroendocrine.”
One question we hear from this community is:
“I have neuroendocrine carcinoma, not a neuroendocrine tumor. Is that different?”
Yes. Neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are both part of the broader family of neuroendocrine neoplasms (NENs), meaning they arise from cells with neuroendocrine features. But NETs and NECs are not simply different names for the same disease. They are biologically distinct cancers, with different behaviors, treatment approaches, and outcomes. Understanding which diagnosis a patient has is one of the most important first steps in planning care.
NET and NEC: What’s the difference?
A neuroendocrine tumor is well-differentiated. That means the cancer cells still resemble neuroendocrine cells in important ways when viewed under the microscope. NETs can be slow-growing, although some are more aggressive.
A neuroendocrine carcinoma is poorly differentiated. That means the cancer cells look and behave much less like normal neuroendocrine cells. NECs are high-grade, faster-growing cancers. They may be classified as small cell NEC or large cell NEC, depending on how the cells look under the microscope.
This distinction is important because it influences prognosis, imaging, treatment options, and clinical trial eligibility.
Grade and differentiation are related, but they are not the same thing
One source of confusion is the word “high-grade.” Grade is one way doctors describe how fast a cancer appears to be growing. Cancer cells grow by making copies of themselves, a process called cell division. When many tumor cells are actively dividing, the cancer may grow and spread more quickly and may behave more aggressively. A common marker used in pathology reports is Ki-67, which estimates the percentage of tumor cells that are actively growing and dividing.
Differentiation is different. It describes how much the cancer cells resemble normal cells of that tissue type.
This is why it is possible to have:
- A well-differentiated NET that is low-grade or intermediate-grade, called NET G1-G2
- A well-differentiated NET that is high-grade, called NET G3
- A poorly differentiated NEC, which is always high-grade
This distinction is especially important because a high-grade, well-differentiated NET may not behave the same way or respond to the same treatments as a poorly differentiated NEC, even though both are high-grade.
When expert pathology review should be considered
In many cases, the distinction between NET and NEC is clear. But in high-grade disease, it can sometimes be difficult to distinguish a well-differentiated NET G3 from a poorly differentiated NEC. Both can have a high Ki-67, but they are biologically different diseases.
Pathologists look at more than Ki-67 alone. They also evaluate how the tumor cells look under the microscope and may use additional pathology or molecular testing to help clarify the diagnosis. Because this distinction can affect treatment decisions, patients with high-grade neuroendocrine cancer may benefit from review by a pathologist and multidisciplinary team with experience in neuroendocrine neoplasms.
Why treatment may be different
Many well-differentiated NETs have somatostatin receptors on the surface of their tumor cells. These receptors act like treatment targets. Somatostatin analogs, such as octreotide and lanreotide, bind to these receptors and are commonly used in many well-differentiated NETs to help control symptoms and, in some cases, slow tumor growth. PRRT also relies on somatostatin receptors to deliver radiation directly to receptor-positive tumor cells.
Well-differentiated NETs may also be treated with surgery, liver-directed therapy, targeted therapies, chemotherapy, or carefully sequenced combinations of treatment, depending on tumor site, grade, symptoms, somatostatin receptor expression, disease burden, pace of growth, and prior treatments.
NECs are different. They tend to grow more quickly, have distinct biology, and may have fewer or more variable somatostatin receptors. Because of this, somatostatin receptor-targeted treatments are generally used much less often for NECs than for well-differentiated NETs. Treatment for NEC often includes platinum-based chemotherapy, such as regimens commonly used for small cell lung cancer, although the best approach can vary by tumor site, small cell versus large cell morphology, molecular features, prior treatments, disease extent, pace of growth, and treatment goals.
Why imaging may be different
Imaging decisions may also differ between NETs and NECs.
FDG PET may be useful in many high-grade NECs because faster-growing tumors often show increased glucose metabolism. However, not every patient with NEC will necessarily need FDG PET. Imaging depends on the tumor type, tumor site, stage, symptoms, prior imaging, treatment question, availability, and whether the result would change management.
DOTATATE PET is most useful when tumors express somatostatin receptors on their surface. Many well-differentiated NETs express these receptors, which is why DOTATATE PET is often helpful in NET care. NECs, and some higher-grade NETs, may have lower or more variable somatostatin receptor expression, making DOTATATE PET less informative in some cases. However, this is not absolute. Some high-grade tumors still show meaningful somatostatin receptor expression, so imaging decisions depend on the specific tumor and clinical situation.
In selected cases, doctors may use both FDG PET and DOTATATE PET. When both scans are used, the goal may be to understand whether the disease has mixed biology. DOTATATE PET can show whether tumors have the target used for somatostatin receptor imaging and some forms of radioligand therapy. FDG PET can help identify more metabolically active and aggressive disease.
Both imaging modalities may be useful when:
- A high-grade NET or NEC is being evaluated and the care team wants to know whether tumors are somatostatin receptor-positive, FDG-avid, or both
- PRRT is being considered, but doctors want to know whether all areas of cancer appear targetable by DOTATATE or whether some areas look more aggressive on FDG PET
- Disease is progressing faster than expected for a well-differentiated NET
- Different lesions appear to behave differently, with some growing quickly while others remain stable
- Conventional imaging, symptoms, tumor markers, or pathology do not fully match the clinical picture
What research is teaching us about NECs
NECs urgently need more research. Compared with many well-differentiated NETs, NECs have fewer effective long-term treatment options. Scientists are studying NECs in two complementary ways.
One approach looks for shared vulnerabilities among aggressive neuroendocrine carcinomas. DLL3 is an important example. DLL3 is a protein expressed in many small cell lung cancers and other high-grade neuroendocrine cancers, and it has become a major therapeutic target. The DLL3-targeting T-cell engager tarlatamab is approved for adults with extensive-stage small cell lung cancer whose disease has progressed on or after platinum-based chemotherapy. Researchers are now studying whether DLL3-targeted treatment may also help patients with other DLL3-expressing neuroendocrine neoplasms, including extrapulmonary NECs and selected DLL3-expressing NETs.
Another recent laboratory study, Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade, examined small cell cancers with neuroendocrine features across different tissue types. The researchers found that loss of the tumor suppressor RB was linked to dependence on a transcription factor called E2F3. In the study, E2F3 dependency was shared across RB-deficient small cell cancer cells from multiple tissues, suggesting a possible vulnerability that could be explored for future therapeutic development.
A second approach studies NECs by site of origin, such as lung, gastrointestinal, gynecologic, genitourinary, or other primary sites. This matters because NECs are not all the same. Even within lung neuroendocrine carcinomas, newer classification work shows important biological subgroups, including differences within large cell neuroendocrine carcinoma and small cell lung carcinoma. A recent IASLC update, IASLC Update on Classification of Pulmonary Neuroendocrine Neoplasms, highlights this growing complexity in lung neuroendocrine neoplasms and the importance of more precise classification.
Both approaches are needed. Shared biology may reveal treatment strategies that apply across multiple NEC types. Site-specific biology may help explain differences in risk factors, molecular drivers, imaging patterns, treatment response, and clinical trial design. Ultimately, the goal is not to treat all NECs as interchangeable, but to understand both what they have in common and what makes each subtype distinct.
Why pathology details matter
For patients with NEC or suspected NEC, the pathology report is especially important. Patients may want to ask their care team:
- Is my diagnosis a well-differentiated NET or a poorly differentiated NEC?
- What is the Ki-67?
- If it is NEC, is it small cell or large cell?
- Would additional pathology testing help clarify the diagnosis, especially if there is uncertainty between NET G3 and NEC?
- Has molecular testing, such as next-generation sequencing, been done on my tumor, and could the results point to any targeted treatments or clinical trials?
- Was my tumor tested for somatostatin receptor expression, and could somatostatin receptor-targeted treatment have any role?
- Should I have FDG PET, DOTATATE PET, or both, and what question would each scan help answer?
- Are there clinical trials for my tumor type, tumor site, grade, or molecular profile?
- Should my case be reviewed by a NEN specialist or a multidisciplinary tumor board?
These questions are not meant to replace medical advice. They are meant to help patients have informed conversations with their care team.
NETRF’s perspective
NETRF funds and follows research across the full spectrum of neuroendocrine cancer, including NETs and NECs. We know that patients with NEC often face urgent treatment decisions, uncertainty, and a lack of disease-specific information.
We also know that terminology is important. When patients understand the difference between NET and NEC, they are better equipped to ask informed questions and understand why their treatment plan may look different from someone else’s in the neuroendocrine cancer community.
NEC research remains a critical need. Progress will require better models, better biomarkers, more clinical trials, and research that connects tumor biology to treatment response.
Bottom line
Neuroendocrine tumors and neuroendocrine carcinomas are related, but they are not the same. NECs are more aggressive, are treated differently, and urgently need more research.
Understanding the diagnosis, including Ki-67, tumor site, imaging profile, and molecular features, can help patients and clinicians make more informed treatment decisions.
At NETRF, we believe every part of the neuroendocrine cancer community deserves research, education, and hope. We will keep pushing for better treatments, better answers, and, ultimately, cures for every person facing neuroendocrine cancer.
For more on NEC diagnosis and treatment, listen to NETRF’s NETWise episode, Understanding Neuroendocrine Carcinoma. Caregivers may also find Care for the Neuroendocrine Carcinoma Caregiver helpful.