Extrapulmonary neuroendocrine carcinomas (EP-NECs) are rare, biologically aggressive malignancies that can arise across multiple organ systems. Their rarity, complex classification, and limited treatment options can make management particularly challenging for oncology teams. However, emerging data on delta-like ligand 3 (DLL3)-targeted therapies—especially T-cell engager approaches—offer a promising direction for this underserved population.

Recently, Andrew Hendifar, MD, the Medical Director of Pancreatic Cancer at the Samuel Oschin Comprehensive Cancer Center at Cedars-Sinai Medical Center, and Danielle Hutchings, MD, an Assistant Professor of Pathology and Laboratory Medicine at Cedars-Sinai Medical Center, co-chaired the i3 Health activity, Clinical Challenges in Extrapulmonary NEC: Expert Insights on Diagnosis, Treatment, and Emerging Targets. In this follow-up interview, they review updates and advancements in the ever-evolving treatment landscape, the role of DLL3 testing, and the importance of multidisciplinary collaboration in EP-NEC care.

EP-NEC is Distinct From Site-Specific Carcinomas

One of the central challenges in EP-NEC management is recognizing that these tumors should not necessarily be treated according to their organ of origin. Although EP-NECs may arise in genitourinary, gastrointestinal, or other extrapulmonary sites, their histology and biology often require a neuroendocrine carcinoma–specific treatment approach.

“The most difficult thing is that it's probably a rare entity and the clinician might not be so sure of themselves how to treat it,” Dr. Hendifar explained.

Clinicians may be tempted to follow treatment algorithms associated with the primary organ site. However, Dr. Hendifar emphasized that if a tumor is confirmed as a neuroendocrine carcinoma, “regardless of the site of origin, you really should treat it that way.”

This distinction is essential because these tumors have “their own therapeutic pathway,” even when they occur in organs more commonly associated with other malignancies.

Accurate Classification is Essential

Correct pathologic classification is a critical first step in determining prognosis and treatment. Dr. Hutchings emphasized the importance of distinguishing well-differentiated neuroendocrine tumors from poorly differentiated neuroendocrine carcinomas.

“People can have a hard time with understanding the tumor classification and associated terminology,” she noted.

Although both are classified as neuroendocrine neoplasms, well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas are biologically distinct entities. They differ in clinical behavior, prognosis, and therapeutic management.

Dr. Hutchings noted that reviewing the key pathologic and clinical features that distinguish these entities is particularly valuable because they have “a differing prognosis as well as treatment algorithm.”

Close communication among pathologists, medical oncologists, radiologists, and other members of the multidisciplinary care team is therefore essential to ensure that patients receive an accurate diagnosis and an appropriate treatment plan.

DLL3: A Promising Therapeutic Target

DLL3 has emerged as a potentially important target in EP-NECs. DLL3-directed therapies have already demonstrated activity in small cell lung cancer, a disease that often informs therapeutic approaches for poorly differentiated neuroendocrine carcinomas.

“The treatment for extrapulmonary neuroendocrine carcinoma typically follows small cell lung cancer pathways,” Dr. Hendifar explained. “And DLL3-targeted therapy works very well in small cell lung cancer.”

Early studies of DLL3-targeted therapy in EP-NECs have produced encouraging results. Dr. Hendifar highlighted particular interest in T-cell engager therapies, which recruit T cells to recognize and attack DLL3-expressing tumor cells.

“Recent data is coming out showing that in certain subgroups, including those with GU malignancies, T-cell engager therapy is very promising,” he said.

Importantly, EP-NECs may prove particularly responsive to these approaches. Dr. Hendifar noted that some mechanisms that limit response in small cell lung cancer, including tumor heterogeneity and resistance pathways, may not apply to the same extent in EP-NECs. This possibility could raise the ceiling of effectiveness for DLL3-targeted T-cell engager therapy in this population.

Unresolved Questions in DLL3 Testing

Despite its potential, several issues must be resolved before DLL3-directed therapy can be fully integrated into routine EPNEC care. A central question is the appropriate threshold for DLL3 expression by immunohistochemistry (IHC).

Dr. Hutchings noted that studies have used varying definitions of DLL3 positivity. Some have considered staining in more than 1% of tumor cells to be positive, while others have differentiated between low and high expression using thresholds of 50% or 75%.

“Determining what that optimal IHC threshold would be will be important for the future,” she said.

Dr. Hendifar agreed, emphasizing that the necessary level of expression for treatment benefit remains uncertain. “What is enough? Is it 1%? Is it 10%? Is it 50%?” he asked.

Testing access is another practical challenge. At many institutions, DLL3 IHC is currently performed as a send-out test through large reference laboratories. As prospective studies mature and interpretive criteria are standardized, broader availability may facilitate more timely treatment decisions.

Clinical Trials May Expand Treatment Options

Clinical trial enrollment will remain central to advancing EP-NEC care. Ongoing studies are evaluating both single-agent T-cell engagers and combinations of T-cell engager therapy with chemotherapy.

“I anticipate that there'll be several approvals to use these treatments in first-line and in refractory disease,” Dr. Hendifar said.

Given the limited treatment landscape for EP-NECs, successful trial results could provide meaningful new options in both treatment-naïve and relapsed or refractory settings. For clinicians, recognizing eligible patients early and facilitating referral to specialized centers or trial sites may be critical.

A Multidisciplinary Approach to an Evolving Field

Both speakers stressed that EP-NEC care benefits from a multidisciplinary perspective. The rapidly evolving literature can be challenging to navigate, especially for rare cancers, but collaboration across specialties helps improve diagnostic precision and treatment planning.

“Learning from colleagues across different specialties can really deepen our understanding of these tumors and hopefully result in better outcomes for patients,” Dr. Hutchings said.

Dr. Hendifar acknowledged the difficulty of keeping pace with continual scientific advances but offered an encouraging perspective. Although new research emerges rapidly, EP-NECs currently has a relatively straightforward treatment paradigm and limited options, which may make integration of effective new therapies more manageable.

As DLL3-targeted therapies and other novel approaches move through clinical development, continued education, multidisciplinary coordination, and clinical trial participation will be essential to translating progress into better patient outcomes.

Key Takeaways

EP-NECs are a rare, distinct malignancy that should generally be treated according to neuroendocrine carcinoma biology rather than organ of origin.
Accurate distinction between well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas is essential.
DLL3-targeted T-cell engager therapies are emerging as a promising strategy, with early activity reported in EP-NECs.
Standardization of DLL3 IHC thresholds and broader test availability are needed to guide treatment selection.
Clinical trial enrollment and multidisciplinary collaboration remain crucial to advancing care for patients with EP-NECs.

About the Speakers

Andrew Hendifar, MD, is the Medical Director of Pancreatic Cancer at the Samuel Oschin Comprehensive Cancer Center at Cedars-Sinai Medical Center. His clinical and research interests include advancing therapeutic strategies and clinical trial access for patients with rare and aggressive neuroendocrine malignancies.

Danielle Hutchings, MD, is an Assistant Professor of Pathology and Laboratory Medicine at Cedars-Sinai Medical Center. Her work focuses on accurate tumor classification, biomarker assessment, and the pathologic features that guide personalized treatment planning for neuroendocrine neoplasms.

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