and ATRX mutations were more likely to have CIN and patients with this subtype of PENs had a

reduction in survival.

Table 56-3 Familial Genetic Syndromes Associated with Pancreatic Endocrine

Neoplasms (PENs)

This landmark sequencing work underscored the potential clinical importance of mutations in the

mTOR pathway in a subset of PEN patients. As a reminder, the drug rapamycin targets mTOR, and thus,

this finding should provide the framework in which we may stratify PEN patients for TOR inhibitor–

based therapies (e.g., everolimus).33 As this work demonstrated that mTOR dysregulation may be an

important predictive marker, others have shown that in a large panel of neuroendocrine tumors (195 of

which only 19 where pancreatic) mTOR overexpression and/or its downstream-activated targets were

associated with worse clinical outcomes (i.e., adverse prognostic markers).37 This work provides

another instance where a poor prognostic marker (for even development of disease) may serve

counterintuitively as a positive predictive marker (for everolimus); an established biomarker, BRCA2,

acts in a similar fashion.

Table 56-4 Portal Vein Sampling

Genetic Links and Syndromes Related to PENs

Significant progress has been made in the genetic understanding of the MEN-1 syndrome in relation to

PENs.38 Chromosomal linkage studies have localized the genetic defect to the 11q13 locus, and studies

of DNA markers have localized the MEN-1 gene between PYGM and D11S97. The gene contains 10

exons that code for a 610-amino-acid protein called menin, whose function is unknown, although it is

classically labeled as a tumor suppressor gene. Some studies provide a possible explanation for loss of

this gene in neuroendocrine tumors.39 The menin protein is expressed in diverse tissues and is highly

conserved evolutionarily. Menin is predominately a nuclear protein, which binds to JunD and may

repress JunD-mediated transcription. Studies in patients with MEN-1 have shown allelic deletions at

chromosome 11q13 in nearly 100% of parathyroid tumors, 85% of nongastrinoma islet cell tumors, and

up to 40% of gastrinomas. In patients with sporadic tumors (without MEN-1), 11q13 deletions are seen

in about 25%, 20%, and almost 50% of parathyroid tumors, nongastrinoma PENs, and gastrinomas,

respectively. Recently it has been shown that a comprehensive genetic testing program for patients at

risk for MEN-1 can identify patients harboring a MEN-1 mutation almost 10 years before the

development of clinical signs or symptoms of disease.40 Since MEN-1 loss has been detected in both the

sporadic and the familial forms of PENs, the menin pathway is most likely involved in the overall

pathogenesis of this disease, whether familial or sporadic in nature.39

Less frequently than MEN-1, PENs may be associated with VHL syndrome. VHL syndrome is another

autosomal dominant inheritance disease that includes many clinical disorders

41 including retinal

hemangioblastomas, cerebellar and medullary hemangioblastomas, and PENs. PENs are found in a small

percentage of patients with VHL syndrome. A mutation in the VHL gene, a tumor suppressor located on

chromosome 3p25–26, which regulates hypoxia-induced cell proliferation, is responsible. Although

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germline mutations with loss of heterozygosity (LOH) are associated with this disease, it has been

proposed that other tumor suppressors most likely cooperate with VHL in order to form PENs. VHLmutated PENs have been shown to have specific defects in angiogenesis and hypoxia-inducible factor

pathways.42

NF-1 (von Recklinghausen disease) is an autosomal dominant disorder that produces a well-described

clinical syndrome characterized by café-au-lait spots and neurofibromas. These patients may develop

pancreatic somatostatinomas, often near the ampulla of Vater. The NF-1 gene is a tumor suppressor

gene located on 17q11.2 that encodes for neurofibromin, a regulator of the mammalian target of

rapamycin (mTOR) pathway. Loss of NF-1 results in mTOR activation and tumor development.43,44

Complementary Progression Modeling

Based on the data from the Marinoni study that attempted to molecularly subtype PENs,36 a stepwise

progression model of PENs were put forth: (1) initiation occurs (unknown mechanism); (2) DAXX/ATRX

mutations induce transformation; (3) alternative lengthening of telomere (ALT)45 activation and CIN;

(4) clonal heterogeneity and a selection of clones; and (5) metastases.36 Complementary to this work,

Zhang described a “double hit model” of PEN progression35 wherein a first mutational hit (e.g., MEN1

or p53) can induce cell cycle progression, even under harsh tumor microenvironment conditions (low

glucose). Then, the second hit (ATRX and mTOR) can cause cell growth and enhance cell invasion and

metastatic potential,35 even in the absence of cell–cell adhesion. These models highlight our recent and

enhanced knowledge of the molecular etiology of PEN. However, future work will need to define the

main initiating event that sets the stage for PEN transformation. Since KRAS activation appears to be

unnecessary, other nonclassical genetic events (e.g., epigenetics and posttranscriptional gene regulation)

should be surveyed as critical key events in this tumorigenesis process.

Molecular Targeting of PENs

In summary, PENs are becoming easier to characterize molecularly (and clinically) due to large scale

sequencing efforts and a better understanding behind the molecular biologic aspects of these pancreatic

tumors. Ongoing efforts to search for candidate genes and novel pathways that set the stage for CIN and

initiation of tumorigenesis in these tumors will aid in unraveling the molecular etiology of this disease

and perhaps even better druggable targets (see Table 56-4 for molecular pathways to target in PENs vs.

pancreatic ductal adenocarcinoma). Still, the molecular characterization of these tumors have helped to

pave the way for clinical trials targeting tyrosine kinases (e.g., sunitinib) and the mTOR pathways (e.g.,

everolimus). In fact, recent work explored targeting multiple points throughout the dysregulated

pathway (PI3K/AKT/mTOR) in PENs by combining PI3K inhibitors with mTOR inhibitors and

demonstrated that this combination may break initial and acquired drug resistance in PENs.46 Future

molecular interrogation of PENs combined with these types of preclinical targeting approaches should

continue to move the field closer to a personalized approach to treating PENs with better targeted

therapies.

PRESENTATION AND EVALUATION

There are three primary ways by which patients with PENs come to clinical attention: the incidental

discovery of a mass in the pancreas during cross-sectional imaging, symptoms secondary to the mass

effect of a lesion in the pancreas (i.e., obstructive jaundice or pain), and, as a consequence of the

symptoms of a syndrome associated with a functional PEN. As mentioned previously, incidentally

detected nonfunctional PENs currently comprise the majority of clinically relevant tumors. They are

typically hypervascular on imaging studies such as computed tomography (CT) or magnetic resonance

imaging (MRI). In the absence of any clinical syndrome, these lesions can be managed as any other

incidental pancreatic lesion. Typically, the size of a PEN at discovery guides decision making between

three standard options: serial observation, endoscopic ultrasound-guided biopsy, or definitive surgical

resection. Size greater than 2 cm is a standard stratification measure, with lesions larger than this

usually managed in a more aggressive fashion. If a nonfunctional PEN is suspected, baseline serum

levels of chromogranin A and pancreatic polypeptide can be useful diagnostic markers prior to surgical

resection. Chromogranin A is a 49-kDa protein contained within the neurosecretory vesicles of PENs,

whose levels should be measured prior to surgical resection and are expected to significantly decline in

the postoperative period with removal of the tumor burden. The chromogranin A levels can be tracked

over time to document tumor recurrence, often before the lesions become visible on cross-sectional

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