Evolving Understanding and Management of Poorly Differentiated Neuroendocrine Tumors

John D. Hainsworth, MD

Clinical Advances in Hematology & Oncology

December 2013, Volume 11, Issue 12


Evolving Understanding and Management of Poorly Differentiated Neuroendocrine Tumors 

John D. Hainsworth, MD, Sarah Cannon Research Institute, Nashville, Tennessee 

Poorly differentiated neuroendocrine tumors (PDNETs) are known to arise from a wide variety of sites. These sites include the lung, pancreas, gastrointestinal tract, urinary bladder, prostate, cervix, uterus, and parotid gland, although primary sites other than the lung are rare. PDNETs are often grouped together as “extrapulmonary small cell carcinomas” because in addition to their histologic similarity, this group of tumors shares biologic and clinical characteristics. All are rapidly growing neoplasms with the potential for early metastasis; the majority have distant metastases at the time of diagnosis. Secretion of bioactive peptides, frequent in various low-grade neuroendocrine carcinomas (eg, carcinoids, islet cell tumors), is uncommonly associated with PDNETs, and somatostatin receptor scintigraphy (octreotide scan) is usually negative.

PDNETs are also distinct from low-grade neuroendocrine tumors in their initial sensitivity to traditional cytotoxic chemotherapy. The high response rate to platinum-based therapy was first described in anaplastic carcinoid tumors arising in the gastrointestinal tract; in contrast, platinum-based regimens were inactive against typical carcinoids and pancreatic neuroendocrine tumors.1 Subsequently, responses to platinum-based therapy have been reported in PDNETs arising in a variety of sites, and in PDNETs of unknown primary site.2-4

Neuroendocrine tumors have traditionally been assumed to have a common origin, with a spectrum of biology ranging from carcinoid-type tumors (indolent) to PDNETs (aggressive). However, the molecular biology of neuroendocrine tumors is just beginning to be elucidated, and evidence currently suggests that PDNETs represent a completely different tumor type. Small cell lung cancer, the best studied high-grade neuroendocrine tumor, is characterized by multiple molecular abnormalities; deletions of chromosome 3p are the most common, but deletions of several other chromosomes (eg, 5q, 10q, and 17p) are also frequently seen.5,6 A similar spectrum of chromosomal abnormalities has been described in PDNETs arising from other sites,6 suggesting similarities in molecular biology among these tumors in addition to their clinical similarities. In contrast, well differentiated carcinoids share none of the molecular abnormalities that are common in PDNETs, suggesting a different carcinogenesis.7

The patient described by Sorscher8 had a PDNET arising in the pancreas; he had a typical clinical course, as evidenced by the presence of advanced metastatic disease at diagnosis, initial sensitivity to platinum-based chemotherapy, and subsequent progression of treatment-resistant disease. As pointed out by Sorscher, newer targeted therapies, including agents with activity against low-grade neuroendocrine tumors, have had limited evaluation in PDNETs. Octreotide, a standard part of therapy for low-grade neuroendocrine tumors, has not been systematically studied in PDNETs, although a recent case report described a patient with a pancreatic PDNET and a positive octreotide scan who had benefit with single-agent octreotide.9 Concurrent use of octreotide with chemotherapy is listed as a treatment option in the National Comprehensive Cancer Network guidelines for such tumors, with only anecdotal supporting evidence. However, since the large majority of PDNETs have negative octreotide scans, this treatment has limited applicability.

Clinical evaluation of other targeted agents has been limited to small cell lung cancer, owing to the rarity of other PDNETs. In small cell lung cancer (as in other PDNETs), multiple pathways that are potential targets of currently available therapeutic agents are overexpressed, including the PI3K/mTOR pathway. However, current evidence indicates that most of these abnormalities are “bystander” abnormalities, rather than key drivers of the malignant process. In a single phase 2 trial, everolimus (Afinitor, Novartis)—an mTOR inhibitor with activity against low grade neuroendocrine tumors—had limited activity against small cell lung cancer.10 Inhibition of the c-Kit pathway, which is frequently overexpressed in small cell lung cancer, has also been ineffective.11 Given the marked differences in molecular biology between PDNETs and low-grade neuroendocrine tumors, the failure to identify therapies effective in both types is not surprising.

No substantial improvements in the therapy of small cell lung cancer or other PDNETs have occurred in over 20 years. To improve the therapy of these neoplasms, critical “driver” molecular abnormalities must be identified and exploited. A number of candidates are currently in early clinical testing. Owing to the similar spectrum of molecular abnormalities, it is likely that new targeted drugs that are highly effective against small cell lung cancer will also have activity in the treatment of other PDNETs.


1. Moertel CG, Kvols LK, O’Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer. 1991;68(2):227-232.

2. Fjällskog MLH, Granberg DPK, Welin SLV, et al. Treatment with cisplatin and etoposide in patients with neuroendocrine tumors. Cancer. 2001;92(5):1101-1107.

3. Cicin I, Karagol H, Uzunoglu S, et al. Extrapulmonary small-cell carcinoma compared with small-cell lung carcinoma. A retrospective single-center study.

4. Hainsworth JD, Spigel DR, Litchy S, Greco FA. Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: a Minnie Pearl Cancer Research Network Study. J Clin Oncol. 2006;24(22):3548-3554.

5. Morstyn G, Brown J, Novak U, Gardner J, Bishop J, Garson M. Heterogeneous cytogenetic abnormalities in small cell lung cancer cell lines. Cancer Res. 1987;47(12):3322-3327.

6. Welborn J, Jenks H, Taplett J, Walling P. High-grade neuroendocrine carcinomas display unique cytogenetic aberrations. Cancer Genet Cytogenet. 2004;155(1):33-41.

7. Swarts DR, Ramaekers FC, Speel EJ. Molecular and cellular biology of neuroendocrine lung tumors: evidence for separate biological entities. Biochim Biophys Acta. 2012;1826(2):255-271.

8. Sorscher S: Metastatic pancreatic poorly differentiated neuroendocrine carcinoma; current treatment considerations. Clin Adv Hemat Oncol. 2013;11(11):748- 749.

9. Sorscher S. Prolonged radiographic stabilization of a metastatic octreotide scan-positive poorly differentiated neuroendocrine tumor using octreotide acetate therapy alone. JCT. 2013;4(7):1148-1149.

10. Tarhini A, Kotsakis A, Gooding W, et al. Phase II study of everolimus (RAD001) in previously treated small cell lung cancer. Clin Cancer Res. 2010;16(23):5900-5907.

11. Krug LM, Crapanzano JP, Azzoli CG, et al. Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial. Cancer. 2005;103(10):2128-2131.

12. Kunnimalaiyaan M, Chen H. Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors. Oncologist. 2007;12(5):535-542.

13. Geffers I, Serth K, Chapman G, et al. Divergent functions and distinct localization of the Notch ligands DLL1 and DLL3 in vivo. J Cell Biol. 2007;178(3):465-476.