Neuroendocrine neoplasms of unknown primary site

INTRODUCTION — Cancer of unknown primary site (CUP) accounts for approximately 2 percent of all invasive cancers [1]. Within this category, tumors from many primary sites with varying biology are represented. Neuroendocrine neoplasms (NENs) constitute less than 5 percent of all CUPs [2]. (See "Overview of the classification and management of cancers of unknown primary site".)

NENs are a heterogeneous group of neoplasms that differ in biologic behavior, histologic appearance, and response to treatment (table 1). Several types of these neoplasms (eg, well-differentiated neuroendocrine tumors (NETs) of the tubular gastrointestinal tract [previously referred to as carcinoid tumors] and pancreas [pancreatic NETs or PNETs], medullary thyroid cancers, pheochromocytomas) are characterized by slow growth and frequent secretion of hormones or vasoactive substances [3-5]. In most cases, these tumors also have typical histologic appearance and are accurately diagnosed with standard pathologic methods (light microscopy and immunohistochemical staining). Others, as typified by small cell carcinoma of the lung, are highly aggressive neoplasms, classified as neuroendocrine carcinomas (NECs), and are usually advanced when diagnosed. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system".)

This review will cover the evaluation and treatment of patients with biopsy-proven metastatic NENs of unknown primary. The diagnostic workup of rare patients who present with symptoms suggestive of an underlying neuroendocrine hormonal syndrome (eg, flushing, diarrhea, hypoglycemia, hyperglycemia) is discussed elsewhere. (See "Diagnosis of carcinoid syndrome and tumor localization" and "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Functionality and nomenclature'.)

EPIDEMIOLOGY — Neuroendocrine neoplasms (NENs) of unknown primary site are relatively uncommon, accounting for 10 to 14 percent of all NENs:

●In a review of over 35,000 patients diagnosed with NENs over a 31-year period (most had well-differentiated tumors arising from the gastrointestinal tract), a primary site could not be found or classified in only 13 percent [6].

●In another series of 750 patients with NENs seen over a 24-year period at a single institution, 82 (10 percent) were of unknown primary site [7].

●In a prospective one-year survey among French pathologists (the PRONET study), 190 of 1340 cases of NENs (14 percent) were classified as NENs with an unknown primary site [8]. Ninety-one (48 percent) were well differentiated, five were moderately differentiated, and 84 (44 percent) were poorly differentiated.

PATHOLOGIC CLASSIFICATION — Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies. Clinical behavior and prognosis correlate closely with histologic differentiation and grade. The World Health Organization (WHO) classifies well-differentiated gastroenteropancreatic NETs into low-grade (G1), intermediate-grade (G2), and high-grade (G3) categories based on histologic appearance and proliferative rate (as assessed by mitotic count and/or Ki-67 labeling index) (table 2) [9]. Many well-differentiated G1 or G2 NETs have a generally indolent clinical behavior. All poorly differentiated neuroendocrine neoplasms (NENs) are G3 neuroendocrine carcinomas (NECs), with an aggressive clinical course. The clinical behavior of the small subset of well-differentiated NETs that have a high proliferative rate (NET, G3) is midway between these two entities. This uniform grading scheme applies to unknown primary site tumors unless a different primary site (eg, the lung) is found [9]. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Classification and terminology' and "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade, well-differentiated tumors (NET G3)'.)

Poorly differentiated NECs are often widely metastatic, and they rarely produce symptoms related to secretion of bioactive substances. Some of these have a histology similar to small cell carcinoma of the lung; a large cell neuroendocrine variant also exists. Some poorly differentiated NECs lack morphologic features of neuroendocrine differentiation [10]. Diagnosis of these cancers depends on immunohistochemical staining for chromogranin and/or synaptophysin. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'Pathologic diagnosis'.)

Accurate distinction of well-differentiated, indolent tumors from poorly differentiated, aggressive tumors and well-differentiated, G3 tumors is important since treatment approaches are different. (See 'Evaluation and management' below.)

CLINICAL PRESENTATION AND PRIMARY SITES — NENs of unknown primary site, especially well-differentiated NETs, often present initially with liver metastases, and most (but not all) represent gastroenteropancreatic NETs [11]. In some patients, the primary site is subsequently identified in the intestinal tract or the pancreas. Patients with mesenteric masses on imaging scans and no evidence of disease on upper or lower endoscopy can be considered to have small intestinal primary tumors and should be treated according to guidelines for small intestinal NETs.

Just as immunohistochemistry and molecular cancer classifier assay (MCCA) can aid in identifying a tumor as having a neuroendocrine origin, these tests may also help to localize the site of origin [12-14]:

●TTF-1 is expressed in most poorly differentiated NECs and some well-differentiated NETs of lung origin. However, an important caveat is that TTF-1 expression can also be detected in other extrapulmonary poorly differentiated NECs [15].

●CDX2 may be expressed in well-differentiated NETs of intestinal origin [16,17]; it may also be found in poorly differentiated lung NECs, especially in the large cell subtype [18].

●Expression of ISL1 is commonly considered a marker of pancreatic origin, although it may be expressed in extrapancreatic poorly differentiated NECs [15].

●Positivity for PAX8 or ISL1 suggests pancreatic, duodenal, or rectal origin [19].

●A 92-gene MCCA is quite accurate in the diagnosis of specific NENs [14]; however, some NENs have gene expression patterns that overlap, and a specific diagnosis cannot be made.

Although immunohistochemistry stains and a MCCA often aid in the diagnosis of the likely site of origin of a NEN it is important to remember that none of the immunohistochemistry stains listed above is definitive, and a MCCA may suggest several NENs as diagnostic possibilities.

A more detailed discussion of the pathology and classification of NENs arising in the digestive tract and lung is available elsewhere. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system" and "High-grade gastroenteropancreatic neuroendocrine neoplasms" and "Pathology of lung malignancies", section on 'Neuroendocrine tumors'.)

EVALUATION AND MANAGEMENT — The following sections will describe evaluation and management based on the histologic pattern and clinical features of neuroendocrine neoplasms (NENs) of unknown primary site.

Well-differentiated neuroendocrine tumor — Patients with well-differentiated neuroendocrine tumors (NETs) of unknown primary site usually have liver metastases, and clinical syndromes from tumor production of bioactive substances may be apparent [7]. The presence of carcinoid syndrome usually suggests a small intestinal primary NET, although pancreatic and lung NETs can occasionally secrete serotonin and other vasoactive substances associated with carcinoid syndrome. (See "Clinical features of carcinoid syndrome", section on 'Frequency'.)

Initial workup — The initial evaluation should include cross-sectional imaging, somatostatin receptor imaging (preferably with a gallium Ga-68 DOTATATE [Ga-68 DOTATATE], Ga-68 DOTATOC, or copper Cu-64 DOTATATE [Cu-64 DOTATATE] integrated positron emission tomography [PET]/computed tomography [CT] scan), and assay for blood and/or urine tumor markers in patients who have clinical symptoms or signs of a functioning tumor:

●CT may identify a primary site in the lungs, gastrointestinal tract, or pancreas.

Mesenteric masses are usually indicative of a primary tumor located in the small intestine. Most metastatic NET patients whose scans feature a typical-appearing mesenteric mass (image 1) can be presumptively considered to have a small intestinal primary and should be treated according to guidelines for metastatic small intestinal NETs. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Imaging'.)

Magnetic resonance imaging (MRI) is an alternative cross-sectional imaging technique that may be preferred by some clinicians; it is more sensitive than CT for the presence of liver metastases. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Cross-sectional imaging'.)

●Approximately 80 percent of well-differentiated NETs of unknown primary site, including pancreatic NETs (with the exception of insulinomas) and gastrointestinal NETs, have high concentrations of somatostatin receptors and can be detected using somatostatin receptor imaging.

PET with newer somatostatin receptor-targeting radiotracers, such as Ga-68 DOTATATE, Ga-68 DOTATOC, and Cu-64 DOTATATE, is more sensitive than somatostatin receptor scintigraphy with indium-111 (111-In) pentetreotide (OctreoScan), particularly for small tumors [20]. Because of the greater sensitivity, Ga-68 DOTATATE, Ga-68 DOTATOC, or Cu-64 DOTATATE PET/CT is preferred over conventional 111-In pentetreotide scanning for identifying an occult primary site, where available [21,22]. This subject is discussed in detail elsewhere. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)

●If a primary site cannot be identified through these imaging modalities, upper and lower endoscopy (with attention to the terminal ileum) should be performed. While video capsule endoscopy allows for evaluation of the entire small intestine, routine use of capsule endoscopy cannot be recommended due to the risk of bowel obstruction from retention of the capsule at the site of an intestinal NET [23].

●The advent of new systemic treatment options for pancreatic NETs provides an additional impetus to identify an occult pancreatic primary site. Endoscopic ultrasonography represents the most sensitive method for identification of a primary pancreatic tumor in patients with liver metastases who are lacking evidence of a small intestinal primary (such as a mesenteric mass or symptoms of carcinoid syndrome) [24-26].

●As noted above, immunohistochemical staining and/or a molecular cancer classifier assay (MCCA) performed on the diagnostic sample may be informative. As examples, positivity for TTF-1 suggests a lung or thyroid tumor; positivity for CDX2 suggests midgut origin; positivity for PAX8 or ISL1 suggests pancreatic, duodenal, or rectal origin [12,13,17,19]. However, none of these immunohistochemical stains is definitive in terms of identifying the primary site.

The 92-gene MCCA is also useful in this setting, since this assay frequently suggests a specific NEN, even when immunohistochemical staining is not definitive [14]. (See 'Pathologic classification' above.)

●For patients who have symptoms suggestive of carcinoid syndrome, elevated urinary levels of 5-hydroxyindoleacetic acid (5-HIAA) are highly specific for serotonin-producing NETs, most of which will be found in the small bowel (particularly the ileum) if the patient undergoes surgical exploration [27-32]. Otherwise, the clinical utility of biomarker testing is limited. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Biochemical testing for carcinoid syndrome' and "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Serotonin and 5-hydroxyindoleacetic acid (5-HIAA)'.)

Treatment — Well-differentiated NETs of unknown primary site are usually approached similarly to well-differentiated NETs of the tubular gastrointestinal tract. Depending on the clinical situation, appropriate management may include local therapy (eg, surgical exploration for resection of a suspected primary tumor, resection of hepatic metastases, nonsurgical liver-directed therapy for hepatic-predominant disease [eg, hepatic arterial embolization]) or systemic therapy (see "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion" and "Treatment of the carcinoid syndrome", section on 'Somatostatin-analog therapy' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Radiolabeled somatostatin analogs' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Everolimus'):

●Somatostatin analogs (long-acting octreotide or lanreotide) should be considered for inhibition of tumor growth in patients with evidence of somatostatin receptor expression on somatostatin receptor imaging, and for control of symptoms in patients with carcinoid syndrome or other symptoms related to hormone secretion.

●Everolimus can be considered for patients with progressive disease based on data from the RADIANT-4 trial, which demonstrated a significant improvement in progression-free survival (PFS) compared with placebo in patients with well-differentiated nonfunctioning NETs of the lung and gastrointestinal tract (hazard ratio [HR] 0.48, 95% CI 0.35-0.67) [33]. Thirty-six patients in this trial had NETs of unknown primary; in this small subgroup, an HR of 0.50 (95% CI 0.22-1.16) was observed.

●For patients with somatostatin receptor-expressing tumors, peptide receptor radiation therapy (PRRT) using radiolabeled somatostatin analogs such as lutetium Lu-177 dotatate represents a reasonable choice, particularly in light of the results of the NETTER1 study, which demonstrated a highly significant improvement in PFS with lutetium Lu-177 dotatate compared with high doses of long-acting octreotide among patients with progressive midgut NETs (HR 0.21, 95% CI 0.13-0.34) [34].

●The role of chemotherapy (eg, capecitabine/temozolomide) is debated, but it can be considered in patients with clinically aggressive tumors.

High-grade poorly differentiated neuroendocrine carcinoma — Patients with high-grade poorly differentiated neuroendocrine carcinomas (NECs) of unknown primary typically present with widespread metastases. In addition to the liver, common metastatic sites include bone, lung, and brain. Histologic variants include small and large cell NEC (see "High-grade gastroenteropancreatic neuroendocrine neoplasms"). Small cell NECs can arise in extrapulmonary sites, such as the esophagus, cervix, prostate, and bladder. (See "Extrapulmonary small cell cancer" and "Small cell neuroendocrine carcinoma of the cervix" and "Small cell carcinoma of the bladder" and "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

Initial workup — The initial evaluation should include cross-sectional imaging of the chest, abdomen, and pelvis (CT or MRI) [35]. Fluorodeoxyglucose (FDG)-PET scanning is a sensitive imaging modality due to the high metabolic rate of poorly differentiated NECs [36]. On the other hand, somatostatin receptor imaging is relatively insensitive and is not recommended in this setting. Brain MRI should be considered due to the high risk of central nervous system metastases [36,37].

Treatment of metastatic poorly differentiated NECs does not vary significantly based on primary site, and therefore an intensive workup to identify a primary site is not warranted.

Treatment — High response rates (approximately 66 percent) have been well documented using a platinum agent (carboplatin or cisplatin) and etoposide in patients with poorly differentiated NECs at a defined primary site. (See "Extrapulmonary small cell cancer" and "Small cell neuroendocrine carcinoma of the cervix" and "Small cell carcinoma of the bladder" and "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

Similar high response rates to a platinum/etoposide combination have been seen in patients with poorly differentiated NECs of unknown primary site, and this represents a standard approach [2,35,38]. In the largest published series, containing 99 patients, a response rate of 70 percent was observed with platinum/etoposide-based chemotherapy [2].

More recently, immune checkpoint inhibitors have proven useful for high-grade NEC of the skin (Merkel cell carcinoma) [39] and for some patients with small cell lung cancer [40]. Immunotherapy may therefore be useful in other high-grade NECs, but at this time, data remain limited. Programmed cell death protein 1 (PD-1) inhibitor monotherapy is associated with minimal response. Systemic treatment for high-grade poorly differentiated NEC is discussed in more detail elsewhere. (See "Extrapulmonary small cell cancer" and "Small cell neuroendocrine carcinoma of the cervix", section on 'Approach to recurrent or metastatic disease' and "Small cell carcinoma of the bladder", section on 'Metastatic disease' and "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'Metastatic disease'.)

High-grade well-differentiated tumors — As noted above, a small subset of well-differentiated NENs appear well or moderately well differentiated on histologic examination, but they have a high proliferative rate (high-grade NET [NET, G3]). (See 'Pathologic classification' above.)

The optimal treatment for these patients is not established, but platinum-based regimens are generally not as effective as they are with high-grade poorly differentiated tumors. Management of these patients is discussed in detail elsewhere. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade, well-differentiated tumors (NET G3)'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

SUMMARY AND RECOMMENDATIONS

●Pathologic classification

•Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies characterized by variable, but most often indolent, biologic behavior. Clinical behavior and prognosis correlate closely with histologic differentiation and grade.

•The World Health Organization (WHO) classifies well-differentiated gastroenteropancreatic NETs into low-grade (G1), intermediate-grade (G2), and high-grade (G3) categories based on histologic appearance and proliferative rate (as assessed by mitotic count and/or Ki-67 labeling index) (table 2). The clinical behavior of well-differentiated G1 and G2 tumors is generally indolent.

•All poorly differentiated neuroendocrine neoplasms (NENs) are G3 neuroendocrine carcinomas (NECs), with an aggressive clinical course. The clinical behavior of the rare well-differentiated G3 NET is in between these two entities. (See 'Pathologic classification' above.)

●Clinical presentation and origin – Most well-differentiated NETs of unknown primary site present with liver metastases. In some patients, the primary site is subsequently identified in the intestinal tract or the pancreas. Patients with mesenteric masses on imaging scans and no evidence of disease on upper or lower endoscopy can be considered to have small intestinal primary tumors and should be treated according to guidelines for small intestinal NETs. (See 'Clinical presentation and primary sites' above.)

●Evaluation and management

•Well-differentiated tumors

-The initial evaluation should include cross-sectional imaging, usually with multiphase CT, and somatostatin receptor imaging to assist with primary localization. Where available, gallium Ga-68 DOTATATE, Ga-68 DOTATOC, or copper Cu-64 DOTATATE positron emission tomography (PET)/CT is preferred over somatostatin receptor scintigraphy (OctreoScan) because of its greater sensitivity.

-If a primary site cannot be identified through these imaging modalities, upper and lower endoscopy (with attention to the terminal ileum) should be performed. Immunohistochemical stains and a 92-gene molecular cancer classifier assay (MCCA) may help in determining the tissue of origin. Endoscopic ultrasonography can be used to rule out an occult pancreatic primary tumor. (See 'Initial workup' above.)

If a primary site still cannot be identified, we recommend that these patients be managed like those with metastatic well-differentiated nonpancreatic NETs (Grade 1B). (See 'Treatment' above and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth".)

-For patients who have symptoms suggestive of carcinoid syndrome, elevated urinary levels of 5-hydroxyindoleacetic acid (5-HIAA) are highly specific for serotonin-producing NETs (eg, those arising in the small bowel). (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Biochemical testing for carcinoid syndrome'.)

•Poorly differentiated tumors

-Patients with poorly differentiated NECs generally have biologically aggressive tumors. Most either present with or rapidly develop disseminated disease. The initial evaluation should include cross-sectional imaging of the chest, abdomen, and pelvis (CT or MRI) and fluorodeoxyglucose (FDG)-PET scanning. (See 'Initial workup' above.)

-We recommend first-line treatment with carboplatin or cisplatin combined with etoposide, following treatment guidelines for small and large cell NECs of the lung (Grade 1B). (See 'Treatment' above.)

•High-grade well-differentiated tumors – A subset of G3 NENs have a high proliferative rate but appear well or moderately well differentiated on histologic examination (NET, G3). The optimal treatment for these patients is not established, but platinum-based regimens are generally not as effective as they are with poorly differentiated tumors, which are all high-grade. Management of these patients is discussed in detail elsewhere. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade, well-differentiated tumors (NET G3)'.)