Neuroen rine Tumors of The Pancreas NETP

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					Neuroendocrine Tumors of The
Pancreas (NETP) or Pancreatic
   Endocrine Tumor (PET)
          Chien-Wen Chou MD.
  Endocrinology and Metabolism Division
         Chi-Mei Medical Center
              13 April 2007
              Introduction (1)
• Uncommon tumors
• Approximately 1 in 100 000
• Only 1–2% of pancreatic neoplasms
• No gender predilection
• Found in all age groups with a peak incidence
  between 30–60 years of age
• Islet cell tumor
• Arise from multipotent stem cells in the ductal
               Introduction (2)
• Between 30–50% of MEN I and 15% of von-Hippel
  Lindau patients will develop NETP
• NETP belonging to MEN I syndrome present with
  deletions on chromosome 11q13, the site of the
  MENIN gene.
• Somatic mutations on the long arm of chromosome 11
  have been found in 20% of sporadic NETP
• The gene associated with von-Hippel Lindau located on
  chromosome 3p25.2 does not appear to be involved in
  the development of sporadic NETP
                     Introduction (3)
• Functioning tumors
   – With Insulinomas being the most frequent type (up to 70%), followed by
     gastrinomas are the two commonest functioning NETP
   – Insulinomas alone, an incidence of approximately 4 tumors per 1 million
   – The remaining rare functioning NETP include glucagonoma, VIPomas (watery
     diarrhea, hypokalemia, achlorhydria), somatostatinomas, pancreatic carcinoids
     (serotonin), ectopic hypercalcemia syndrome (PTH-rP), and ACTH-secreting
     NETP (Cushing syndrome).
   – Syndromic or functioning PETs make up 60%

• Nonfunctioning NETP
   – may still show elevated hormone levels in the blood and immunoreactivity on
     histological specimens
   – Hormones that to date do not appear to have a clinical syndrome when found
     in excess in the blood include PP, neurotensin, CgA and the newly discovered
     ghrelin, which is a growth hormone secratogue.
   – Up to 40% of NETP are nonfunctioning.
                     Biologic Behavior
•   PETs are potentially malignant neoplasms.
•   with 50–60% having already spread to the liver at presentation.
•   Among the functioning tumors, most insulinomas show benign behavior.
•   other types of functioning tumors fall either into the category of well-
    differentiated tumors with uncertain behavior (10%–15%) or, more
    frequently, that of well-differentiated carcinomas (approximately 85%–
•   Most of nonfunctioning tumors are well-differentiated carcinomas (90%–
•   Poorly differentiated endocrine carcinomas are uncommon
•   In general, malignant metastasizing PETs are slowly growing neoplasms.
•   Survival from the time of diagnosis usually ranges between 2 and 10 years.
•   In sporadic metastasizing gastrinomas, survival is longer if the tumor arises
    from the duodenum than from the pancreas.
•   MEN1-associated tumors of the pancreas are rarely metastatic, in contrast
    to those of the duodenum
 Pathological Classification and Biochemical
• The histological criteria are the degree of differentiation, the size of
  the tumor, the presence or absence of angioinvasion and the
  proliferation index.
• This classification differentiates between well-differentiated, mostly
  benign endocrine tumors with an excellent prognosis (such as
  insulinomas), well-differentiated neuroendocrine carcinomas with a
  low malignant potential and a favorable prognosis (some
  gastrinomas), and poorly-differentiated highly malignant
  neuroendocrine carcinomas with a poor prognosis (many
  nonfunctioning NETP)
• There are general tumor markers that are released by both
  functioning and nonfunctioning NETP, these include CgA, PP and
• CgA is elevated in 50–80% of NETP, and has been shown to
  correlate with overall disease burden
          Somatostatin Recetpors
• Many neuroendocrine tumors, including PETs, express
  somatostatin receptors.
• Five types of these receptors have been identified (eg, SSTR1-
• They can be demonstrated by autoradiography, by
  scintigraphic imaging (OctreoScan) or by
• In PETs, the immunohistochemical expression of SSTR2, which
  shows a membranous pattern, correlates closely with the
  OctreoScan signals (Fig. 1).
• In the group of functioning PETs, gastrinomas are more
  commonly positive for SSTR2/5 (up to 90%) than insulinomas
  are (up to 60%).
FIGURE 1. Membranous immunostaining for the somatostatin receptor SSTR2 in a
pancreatic endocrine tumor (PET).
                   Morphologic Features
   • Macroscopy

FIGURE 2. Gross appearance of a typical pancreatic endocrine tumor that is well
demarcated from the surrounding normal parenchyma.
                    Morphologic Features
    • Histology

FIGURE 3. Pancreatic endocrine tumor with (A) a trabecular and pseudoglandular
pattern, (B) a solid-medullary (“insular”) pattern, and (C) a trabecular pattern and hyaline
stromal sclerosis.
•   Markers of the neuroendocrine phenotype, such as synaptophysin,
    chromogranins A, B, and C, HISL-19, neuron-specific enolase (NSE), the
    proprotein convertases PC2 and PC3, the lymphoreticular epitope Leu-7, and
    the neural cell adhesion molecule (NCAM or CD56), reveal the
    neuroendocrine differentiation of PETs, independent of hormone production.
•   NSE represents a cytoplasmic protein, while synaptophysin belongs to a
    complex family of small vesicle membrane proteins, which also includes
    synaptobrevin, SV2, and SNAP25.
•   The staining intensity of these markers is independent of the content of
    secretory granules in the cells or the type of hormone produced (Fig. 4A).
•   antibodies and antisera directed against the chromogranins, HISL-19, Leu-7,
    prealbumin, and pancreastatin recognize components of neurosecretory
    granules, and thus their staining intensity depends on the granule content (eg,
    grade of differentiation) of the cells (Fig. 4B).
•   The chromogranin A immunoreactivity roughly parallels the results of silver
    staining techniques applied for the detection of argyrophilia.
•   In addition to neuroendocrine markers, PETs stain for cytokeratins 8, 18, and
    19 but rarely for cytokeratin 7 and neurofilament proteins
                 Criteria of Malignancy
•   Gross invasion of adjacent organs and lymph node or liver metastases are
    unequivocal evidence of malignancy in PETs, and poor histologic differentiation
    with a high degree of cellular anaplasia and features of a small cell carcinomas is a
    good indication of malignancy (see Table 3).
•   metastasis may not occur until many years after the surgical excision of the
•   in well-differentiated tumors, tumor size (>2–3 cm), tumor necrosis, microinvasion
    of lymphatic vessels, blood vessels or nerves, a high mitotic index (ie, >2 per 10
    HPF) and high proliferative activity (ie, Ki-67/MIB-1 indices greater than 2 and
    PCNA indices greater than 5%) and tumor biology (insulinoma versus
    noninsulinomas) are strongly correlated with malignant behavior (Table 2).
•   Recently cytokeratin 19 and the entrapment of islets were found to correlate with
•   DNA analysis (ploidy pattern),staining for AgNORs and expression of oncogene
    products, progesterone receptor, laminin receptor, and the [alpha] chain of human
    chorionic gonadotropin (HCG-a) are of minor prognostic
          Specific Tumor Types
• Insulinomas
• Gastrinomas
• Glucagonomas
• Vipomas
• Somatostatinomas
• Functioning Tumors Producing Ectopic Hormones or
  Multiple Hormones
• Nonfunctioning Tumors
• PET in MEN Type 1
• Mixed Endocrine-Exocrine Tumors
• The peak incidence is found between 40 and 60 years.
• Virtually all insulinomas are found in the pancreas. They are
  distributed almost evenly throughout the pancreas or are
  attached to it
• such tumors have been observed in the duodenum, ileum,
  lung, cervix and ovary.
• Between 85% and 99% of insulinomas are benign, solitary,
  and less than 2.5 cm in diameter when detected
• Insulinomas that turn out to be malignant usually have a
  diameter of over 3 cm, and about one third have metastasized
  at the time of diagnosis.
• Multiple insulinomas, occurring synchronously or
  metachronously, are found in 2%–7% of the patients, and
  MEN1-associated insulinomas in 6%
FIGURE 7. Trabecular insulinoma showing amyloid deposition.
•   Inappropriate gastrin secretion by gastrinomas causes the Zollinger-Ellison
    syndrome (ZES).
•   This is characterized by gastric acid hypersecretion, reflux disease, intractable
    peptic ulceration, and occasionally severe diarrhea.
•   Between 60% and 75% of patients with ZES are found to have the syndrome as an
    isolated disease (sporadic ZES); in the remaining patients, ZES is part of the MEN1
•   Gastrinomas are second only in incidence to insulinomas and are most often
•   The peak incidence of gastrinomas lies between 40 and 50 years; children (5–15
    years of age) are rarely affected
•   Around 90% of the gastrinomas associated with the MEN1 syndrome reside in the
    duodenum (Fig. 8).
•   These tumors are usually smaller than 1 cm and multicentric and arise from
    gastrin-cell-precursor lesions
•   Currently, duodenal gastrinomas are more frequently found in the duodenum and
    clearly outnumber pancreatic gastrinomas by 4:1 to 5:1
FIGURE 8. Small submucosal gastrinoma of the duodenum from a patient with a
multiple endocrine neoplasia type 1 (MEN1)-associated Zollinger-Ellison syndrome.
• This syndrome includes a rash known as necrolytic
  migratory erythema, mild glucose intolerance,
  normochromic normocytic anemia, weight loss,
  depression, and a tendency to develop deep vein
• rather large (size range, 2–35 cm), commonly occur
  in the distal portion of the pancreas or attached to
  the pancreas
• most often malignant
• causes the watery diarrhea, hypokalemia, and achlorhydria
  (WDHA) syndrome, also called Verner-Morrison syndrome
• In the adult, most of vipomas are of pancreatic origin.
• Exceptions are some rare VIP-producing pheochromocytomas
  and intestinal endocrine tumors.
• In children, WDHA syndromes have been reported in
  association with VIP-secreting ganglioneuromas and
• usually solitary large tumors (mean size, 4–5 cm), occur often
  in the pancreas tail (approximately 50%), and are malignant in
  at least 80% of cases
• In 1979, the somatostatinoma syndrome was described in
  patients presenting with symptoms of diabetes mellitus,
  cholecystolithiasis, steatorrhea, indigestion, hypochlorhydria,
  and occasionally anemia
• also at other sites, particularly the duodenum
• 50% of the cases, malignant
• occasional psammomatous calcifications
• most often at the site of the papilla of Vater or in close
  proximity to it
• Some of these tumors were associated with
  neurofibromatosis type 1 and ZES/MEN1
     Functioning Tumors Producing Ectopic
       Hormones or Multiple Hormones
• due to the production of ACTH (Cushing syndrome),
  serotonin (carcinoid syndrome), growth hormone-
  releasing factor (acromegaly), PTH-related protein
  (PTHrP) mimicking the action of PTH (paraneoplastic
  hypercalcemia), and calcitonin (diarrhea in 50% of
  the cases).
• Most of these particular neoplasms were malignant
  and of large size.
• Combinations of various hormonal syndromes or
  transitions from one syndrome to another have been
           Nonfunctioning Tumors
• The majority of surgically removed nonfunctioning tumors are
  more than 5 cm in diameter and show malignant behavior.
• Their symptoms are related either to the appearance of
  metastases or to their size and site.
• The explanation for the lack of hormonally induced
  syndromes in these PETs may be
   (1) the low amount of hormone(s) produced and released
   (2) the biologic ineffectiveness of the principal hormone synthesized and
      secreted by the tumor, as is the case with PPomas and
   (3) the secretion by the tumor of a precursor hormone that is
      functionally inert.
             PET in MEN Type 1
• In MEN, PETs are part of a tumor spectrum that
  involves the parathyroid glands (80%–98% of
  patients), the anterior pituitary (9%–40%) and the
  duodenum (40%–85%) but occasionally also the
  stomach, lung, or thymus
• pancreatic lesions in MEN1 is diffuse
  microdenomatosis in association with 1 or several
  macrotumors (above 0.5 cm in diameter).
            Localization Studies
• Biphasic computed tomography scan of the pancreas
  and liver with water as the oral contrast agent, and
  magnetic resonance imaging of the pancreas and liver.
• Endoscopic ultrasound
• Indium-111 octreotide scintigraphy
• I 131mIBG (metaiodobenzylguanidine) scanning has a
  sensitivity of less than 10% for these tumors
• Positron emission tomography (PET) scanning
• 5-hydroxytryptophan labeled with 11C reveals more
  than 95% of NETP
                Surgical Treatment (1)
•   Prior to surgery, symptoms of hormone over-production must be treated.
•   This includes fluid and electrolyte resuscitation in patients with diarrhea
    (glucagonoma and VIPoma).
•   Insulinoma patients should have sugars controlled using diet, octreotide and
    diazoxide when needed.
•   Gastrinoma patients require control of acid overproduction using proton pump
    inhibitors and octreotide.
•   Severely malnourished patients may require supplemental nutrition prior to
    surgical therapy
•   all tumors (except for insulinomas, some gastrinomas and small lesions less than 2
    cm) have a high likelihood of being malignant.
•   NETP should undergo an oncologic pancreatic resection including the surrounding
    lymph nodes.
•   For lesions in the head and neck and of the pancreas, this involves a Whipple
•   lesions to the left of the superior mesenteric vein–portal vein confluence should
    undergo a distal pancreatic resection and splenectom
           Surgical Treatment (2)
• As the majority of insulinomas are benign (90%), these tumors
  should be treated with enucleation when possible.
• Laparoscopic resection of these tumors has recently been
• In cases where there is a suspicion of malignancy, including
  local invasion and/or tumors > 5cm in size, formal pancreatic
  resection should be performed
• 50% of gastrinomas will prove to be malignant especially
  when they exceed 5cm in size.
• Locoregional lymph nodes should be assessed intraoperatively
                  Surgical Treatment
                   (Liver Metastasis)
• In patients with metastatic disease of the liver, the goals of therapy
  are to control and/or eliminate tumor growth, as well as to diminish
  excess hormone production
• As with all metastatic tumors of the liver, surgical resection is
  considered the treatment of choice when possible.
• The utilization of other forms of cytoreduction such as
  radiofrequency ablation and embolization have increased our ability
  to debulk metastatic liver lesions
• most patients will recur within the first 2 years following resection
• Some patients with apparently nonfunctioning NETP, however, will
  progress over time to display an endocrinopathy with progressive
  growth of the tumor
• In patients that demonstrate radiotracer uptake of octreotide or
  MIBG by tumor deposits, our strategy is tumor debulking with
  postoperative adjuvant therapy
     Surgical Treatment (MEN 1)
• Surgical cure is rarely if ever possible without
  complete pancreatectomy because of the
  diffuse adenomatous disease seen through
  the pancreas.
• Treatment of NETP in MEN I was focused on
  the management of various functional
          Nonsurgical Treatment
•   Chemotherapy
•   Somatostatin analogues
•   Interferon-alfa
•   Radiolabeled therapy
• NET are in general chemoresistant.
• NET arising from the pancreas, however, appear to be the
  most responsive.
• Streptozocin combination regimes (streptozocin and
  doxorubicin) achieve a favorable, but short lived response in
  up to 60% of patients
• Streptozocin is a glucosamine-nitrosurea compound that
  induces degranulation of islet b-cells.
• Dacarbazine monotherapy has also shown response rates up
  to 40%
• The combination of etoposide and cisplatin in NETP has been
  used with limited short-lived response rates
         Somatostatin Analogues
• Symptomatic along with biochemical response to
  somatostatin analogue therapy occurs in between 60–90%
  of patients
• The median duration of response, however, is on average
  only 12 months, at which time tachyphylaxis often develops.
• Somatostatin analogues inhibit not only hormone release,
  but also play a role in inhibiting angiogenesis. Between 5–
  15% of patients will have a reduction in tumor burden.
• The future developments of subtype receptor-specific
  analogues show promise
• Targeting somatostatin receptor subtype 3, which is
  involved in angiogenesis
• Interferon acts through both direct
  antiproliferative effects as well as inhibition of
  tumor angiogenesis mediated by suppression of
  VEGF gene expression in NETP
• interferon has shown a 50% biochemical
  response for a median duration of 20 months
• Tumor response occurs in only 10–15% of
  patients, however, tumor stabilization is reported
  in 40–60% of patients.
• Side effects include flu-like symptoms, arthralgias
  and depression.
         Radiolabeled therapy
• Tumor uptake with 111In-octreotide was seen
  in 61% of insulinomas, and 100% of the
  gastrinomas studied
• To date, prospective survival benefit has not
  been demonstrated, however, improvement in
  quality of life for these patients
• The recent development of other radiolabeled
  somatostatin analogues coupled with 90Y and
• NETP have a more indolent course, with a concomitantly better outcome
  when compared with pancreatic adenocarcinoma.
• Prognosis depends on a combination of factors including histopathologic
  differentiation, size of the tumor, and the associated syndrome.
• Using the Surveillance, Epidemiology, and End Results (SEER) program,
  over 13 000 NET of the gastrointestinal tract were examined
• The overall 5-year survival was 50.4%.
• The presence of regional and distant disease reduced this to 21.8%.
• When classified by site of origin, foregut tumors (including pancreas) had
  a 5-year survival of 44.5% (61% midgut, 72% hindgut).
• Other possible prognostic indicators being studied include expression of
  Ki-67, p53, oncoprotein, tumor-suppressor genes, and adhesion molecules
• A low expression of Ki-67, a histopathologic proliferation marker, predicts
  slow tumor growth and a more favorable prognosis
• Elijah Dixon and Janice L. Pasieka
  Functioning and nonfunctioning neuroendocrine
   tumors of the pancreas. [Review]
  Current Opinion in Oncology. 19:30-35, 2007

• Gunter Kloppel and Martin Anlauf
  Pancreatic Endocrine Tumors
  Pathology Case reviews 2006; 11:256-267

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