Molecular analysis of panNET G1 and G2 has revealed several genetic alterations with MEN1, DAXX, and ATRX, being the most common somatic inactivating mutations in these tumors.28–30 MEN1 genetic mutation can be inherited as part of MEN1 syndrome; however, in >35% of cases, MEN1 mutation occurs as a somatic disorder.20,28,29 MEN1 gene encodes a protein, menin, a histone methyltransferase complex, which acts a tumor suppressor. Recent advances have shown that the tumor-suppressing pathway mediated by MEN1 is dependent on the Pi3K-Akt-mTOR pathway mediated by PHLDA3, a novel tumor suppressor gene that inhibits Akt activation. The inactivation of both PHLDA3 and MEN1 the emergence of panNET.31,32
PanNENs can also be classified based on their cell of origin as functioning or N-F tumors. Functioning panNENs abnormally secrete large amounts of peptide hormones and other bioactive compounds leading to hypersecretion clinical syndromes. N-F panNEN, as it names implies, may or may not secrete peptide hormones but at levels insufficient to cause clinical symptoms. Most functioning and N-F panNENs are graded as well-differentiated. Clinicians must be aware of the numerous presentations of these tumors, as the first step to management of these uncommon malignancies is to initially suspect the diagnosis.
Insulinomas are the most common functioning panNET and account for >35% to 40% of this category.2,43 They are composed of insulin-producing and proinsulin-producing β cells actively secreting large amount of insulin resulting in episodic hyperinsulinemia.2,10 These episodic hyperinsulinemias are referred to as Whipple’s triad. Clinically, patients present with various symptoms related to hypoglycemia, including: weakness, tremors, sweating, confusion, blurred vision, and palpitation, which occur during fasting or exercise. They have documented hypoglycemia at time of symptoms with plasma glucose levels <40 to 50 mg/dL. And, their symptoms are resolved with the administration of glucose administration.2,43–47 Other laboratory analysis is needed for the diagnosis of insulinoma, such as prolonged fasting (2 h) with blood glucose measurement, C-peptide, serum insulin and proinsulin.2,47 Insulinomas share the same morphologic and molecular features of panNET at the exception of stromal amyloid deposits, amylin, specific to insulinomas and insulin immunohistochemical labeling (Fig. 5).48 Most insulinomas, >90%, are benign and often cured by surgical resection.45 These benign insulinomas are usually well-differentiated, G1, panNETs with a ki-67 proliferative index <2% and confined to the pancreas. Malignant insulinomas are more often G2 panNETs with a greater ki-67 proliferative index and are characterized by local invasion, lymph node or liver metastasis.10,47,49 In addition to the proliferation index, the most important prognostic factors for panNETs is tumor size.50,51 Insulinomas <2 cm in largest diameter have a 10-year survival rate close to 100%; whereas, those >2 cm see their 10-year survival rate dropped to nearly 30%. Less than 10% of patients have metastasis, usually hepatic, at the time of diagnosis.46
Glucagonoma is a rare pancreatic α-islet tumor and it accounts for up to 5% of panNETs making it the fourth most common functioning panNET, after insulinoma, gastrinoma, and VIPoma.44,52–54 Glucagonomas are well-differentiated panNETs composed of glucagon-producing cells secreting uncontrolled quantities of glucagon in the bloodstream resulting in the glucagonoma syndrome. This syndrome is characterized by clinical triad featuring necrolytic migratory erythema (NME), diabetes mellitus, and weight loss.53,55–57 NME, a zinc deficiency dermatosis, is often the hallmark initial presenting symptom of this disorder and is characterized by histologic necrolysis of the upper epidermis with vacuolated keratinocytes.54,58 NME usually involves the intertriginous areas of the perineum and buttocks then migrates toward the distal extremities and can be associated with angular stomatitis, cheilitis, and atrophic glossitis.54 Other reported clinical features of this syndrome are vulvovaginitis, urethritis, amino acid deficiency, anemia, depression, and venous thrombosis with pulmonary embolism.54,56,59–61 The diagnosis of a glucagonoma requires laboratory validation elevated serum glucagon level, 500 to 1000 pg/mL, and imaging confirming a pancreatic neoplasm.54 On a histomorphologic standpoint, glucagonoma shares the same features as any panNETs. Immunohistochemical stains for glucagon highlights the glucagon-producing neoplastic cells.55 Although most glucagonomas are sporadic, 3% of these tumors are associated with MEN1 syndrome.62
These neoplasms are slow-growing tumors and often diagnosed at an advance stage. More than 70% to 90% are malignant and present with metastases at time of diagnosis, usually involving the liver.55,63,64 Their prognosis depends on stage and grades.52,65 Tumor size and ki-67 proliferative index do not seem to correlate with biological behavior, as most are diagnosed large.52,63,66 Despite the malignant potential of these tumors, the overall 5-year survival rate is estimated close to 70% with tumor growth and mass effect being the main cause of mortality.55,57,63
Gastrinomas are the second most common functioning panNETs and account as many as 20% of cases.77–79 These neoplasms are found in an anatomic location called the gastrinoma triangle, a region between the junctions of cystic and common bile ducts, second and third parts of the duodenum, and neck and body of the pancreas. Gastrinomas are composed of gastrin-producing G cells resulting in excessive gastrin production and a high gastric acid output leading to a clinical syndrome called Zollinger-Ellison syndrome (ZES).80,81 Patients with this syndrome present with severe and extensive peptic ulcer disease, dyspepsia, nausea, vomiting, abdominal pain, and ulcer complications.44,80,82,83 An increased fasting serum gastrin level at basal state or after stimulation is helpful in establishing the diagnosis.44,81,84 As other functioning neuroendocrine tumors, gastrinomas are histologically and molecularly identical in addition to showing diffuse apical immunostaining for gastrin (Fig. 7).85,86 On a prognostic standpoint, >90% of gastrinomas are malignant with one-third presenting metastasis at the time of diagnosis, with liver and bone being common spread site.3,80
VIPomas are a rare tumor accounting for 3% to 5% of functioning panNETs and arise from non-β islet cells of the pancreas that secrete vasoactive intestinal polypeptide.3,44,45 VIP-secreting neoplasms can occur in many regions of the body, including the colon, adrenal glands, liver and bronchus. Nevertheless, >85% are found in the pancreas, predominantly the tail.87 VIPomas are known to produce hypersecretion syndrome, called by many names including Verner-Morrison, watery diarrhea, hypokalemia, and achlorhydria (WDHA), or VIPoma syndrome.3,88,89 WDHA syndrome is characterized watery diarrhea (up to 10 to 15 L), flushing, hyperglycemia, hypocalcemia, and paralytic ileus. Patients suffering from severe secretory watery diarrhea can develop secondary electrolyte disturbances, such as hypokalemia, hypophosphatemia, hypomagnesemia, and metabolic acidosis.90 VIP-secreting neoplasms also inhibit gastric acid production leading to hypochlorhydria or achlorhydria in ∼75% of cases.3,44,90,91 In the absence of a radiologically visible tumor, an increased serum VIP level (>500 pg/mL or >80 pmol/L) and suggestive clinical symptoms, the diagnosis of VIPoma can be established.80,89–91 In addition to routine neuroendocrine markers, about 90% of VIPomas are immunoreactive with VIP immunohistochemical stain. Certain VIPomas can also cross react with additional markers, such as peptide histidine methionine, pancreatic polypeptide, GHRH, α-HCG, insulin, and others.92–95 Most VIPomas, ranging from 70% to 90%, are malignant with 40% to 70% having metastasized at time of diagnosis, especially to the, liver, lymph nodes or bone.90 Although VIPomas are often diagnoses at an advanced stage, the overall 5-year survival rate has been documented as high as 94% in certain studies and drops significantly to <68% in patients with metastases.89,91,96
Serotonin-producing panNETs are extremely rare and ∼100 cases have been documented in literature.97–102 These neoplasms are composed of serotonin-producing cells, which are believed to arise from either enterochromaffin cells, Kulchitsky cells, or from multipotent precursor cells along the pancreatic ducts.97,100 Because of their small number, serotonin-producing tumors or serotonomas are diagnosed based on positive immunoreactivity to serotonin markers, elevated serum serotonin levels or high urine levels of its metabolite 5-hydroxyindoleacetic acid.99,100 Serotonin hypersecretion can cause a carcinoid syndrome, which has been documented predominantly in advanced metastatic disease.99,103–105 In a carcinoid syndrome, patients present with a classic triad of cutaneous flushing, diarrhea, and valvular disease.104,105 Additional symptoms such as asthma, abdominal pain, and weight loss are also common findings.99,105 The overall 1-year survival rate for patients with local disease is up to 84%; however, if metastatic disease is identified, their prognosis significantly drops to 37.5% over the course of 5 years.99,106
ACTH-producing tumors of the pancreas are rare and <150 cases have been reported in literature.107–111 These neoplasms are composed of ACTH-hypersecreting cells, causing ectopic Cushing syndrome. Cushing syndrome involves a wide range of clinical symptoms including significant weight gain with centripetal fat distribution, hypertension, purplish-red skin striae, lower limb edema, and others.112–114 Besides symptoms of Cushing syndrome, patients diagnosed with ACTH-secreting pancreatic neoplasms were also found with additional clinical features of ZES (34.5%), insulinoma syndrome (5%), and carcinoid syndrome (1 patient), caused by concomitant release of gastrin, insulin, and serotonin, respectively.9,107,110 High level of serum ACTH and β-endorphin may help in the diagnosis. Morphologically, these tumors are identical to well-differentiated panNETs and often demonstrate vascular and perineural invasion, which are frequently found in grade 2. Immunohistochemical expression of ACTH, with variable degree and intensity, has been found in most cases, in occasional CD117 immunopositivity which can be associated to a worse prognosis (Fig. 8).107 An extensive literature review performed by Maragliano et al107 has compared the survival rate of ACTH-secreting panNETs to other functioning panNETs. The overall 5-year survival rate of ACTH-secreting panNETs is quite poor and estimated at 35%, compared with 97% for insulinomas,72% for gastrinomas, and 75.2% for somatostatinomas, and 80% for N-F panNETs.107
As previously stated, the term N-F panNEN is reserved for neuroendocrine neoplasms occurring in patients with no paraneoplastic symptoms related to tumor hormone hypersecretion. Recent advances in imaging modalities are responsible for an important increased number in the diagnosis of incidental N-F panNEN causing its relative frequency, in some studies, to reach as high as 70% to 90% of panNENs.17,115–119 Excluding incidental cases, N-F panNEN symptomatology is usually related to its mass-related burden of the primary disease or metastasis. Most of these tumors are located in the head of the pancreas resulting in biliary obstruction, gastric outlet obstruction, pancreatitis, postobstructive jaundice, and nonspecific abdominal pain. Immunomorphologic features of N-F panNENs are consistent with those of well-differentiated panNETs, as these tumors demonstrate positive expression of neuroendocrine markers. Although not associated with hypersecretory syndromes, N-F tumors may express various peptide hormones on immunohistochemical studies, such as glucagon, somatostatin, and serotonin.120–122 Most N-F panNENs occur sporadically, nearly 10% are associated with predisposing genetic syndromes, including MEN1, von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC).123 N-F panNENs are a heterogenous group of disease and range from slow-growing noninfiltrative tumors to rapidly metastasizing malignancies. Because of their lack of paraneoplastic symptoms, many N-F panNENs are generally diagnosed at more advanced stages.51,115,116,124,125 As consequence, N-F panNEN presents with distant metastases in up to 50% of patients.126 Metastatic disease primarily occurs in the liver, although other sites including bone, peritoneum, adrenal, brain, and spleen have been documented.127 Surgery should be considered for all patients for whom complete resection is possible, while liver directed therapies are useful for managing hepatic metastases.125,128
Neuroendocrine pancreatic cancers can occur as part of inherited tumor syndromes.129,130 There are 4 well-established syndromes associated with inherited panNETs. These include MEN1, VHL, NF1, and TSC, and altogether, these syndromes account for ∼10% to 20% of well-differentiated panNETs (Table 3).1,20,129,131–135 Unlike their sporadic counterparts, syndromic panNENs are usually diagnosed as a multifocal disease.
MEN1 is an inherited autosomal dominant disorder characterized by mutations in the MEN1 gene mapped to chromosome region 11q13 and encoding for the nuclear protein menin. MEN1 gene is classified as a gatekeeper tumor suppressor and directly controls cellular proliferation, regulation and death.131,133,136–143 Patients with MEN1 syndrome are at higher risk to develop several endocrine tumors at a young age, over 90% by the age of 40 years old.129 These endocrine neoplasms frequently arise in the parathyroid glands (95%), anterior pituitary (up to 40%), and pancreatic islet and duodenum (40% to 80%).129,144,145 In the pancreas, these tumors are usually multicentric, occur in any parts, head or tail, and range in size from microadenomas to macroadenomas. Their biological behavior also varies from benign to invasive and metastatic carcinomas.146,147 The most commonly encountered panNENs in MEN1 are N-F panNENs; however, insulinomas, gastrinomas, glucaconomas, and rarely VIPomas and somatostatinomas are also observed.78,133,134,137,147–150 In addition to their typical neuroendocrine morphology, MEN1-associated panNENs may present with foci of nesidioblastosis in addition to ductuloinsular complexes. As any other neuroendocrine tumors, these tumors reveal positive immunolabeling for neuroendocrine markers and their respective pancreatic hormone polypeptide markers.133
Compared with their sporadic counterpart, some MEN1-associated panNENs exhibit a more aggressive potential behavior with metastatic disease reported in 23% to 33% of cases.77,151–153 For these MEN1 syndromic tumors, tumor size at time of presentation is an important prognostic factor shown to influence both progression and overall survival, as tumors with a diameter larger than >1.5 to 2 cm are associated with a higher risk of malignant involvement.147,153 Even in presence of metastatic disease, long-term survival has been documented in MEN1 patients, suggesting a slow progression in this disease. Nevertheless, pancreatic cancer remains the main cause of disease-related death in MEN1, with a probability of death of 50% by the age of 50 years, if not treated.147,151,153–155 Early panNEN diagnosis is essential in patients with MEN1 syndrome, as these neoplasm have a significant impact on life expectancy and morbidity.
VHL syndrome is an inherited autosomal dominant condition caused by mutations in VHL gene, a tumor suppressor, mapped on chromosome region 3p25. VHL gene function involves the oxygen-sensing pathway through hypoxia-inducible factors.129,133,156–159 Mutations in this gene lead to the emergence of several tumors in various organs, including hemangioblastomas of the retina and craniospinal region (>70%), pancreatic lesions (35% to 72%), renal tumors (up to 60%) pheochromocytomas (10% to 20%), and endolymphatic sac tumors (10%).133,159–161 Presence of VHL-associated panNEN has been described in about 10% to 17% of syndromic patients. Most neoplasms are diagnosed at a young age, mean of 38 years and present usually as multifocal lesions dispersed along the pancreas.161–165 N-F panNETs are the most frequently identified type with rare cases of insulinoma, glucagonoma, VIPoma, and somatostatinoma reported.162,166–168 In addition to classic neuroendocrine morphology, these tumors may present with a trabecular, glandular and/or solid architecture and other histological features, such as hypervascularity, nuclear atypia, and clear/multivacuolated cell changes. These distinctive findings are attributed to the pseudohypoxia state caused by the activation of HIF in VHL syndrome.169 Compared with sporadic panNENs, resected VHL-associated panNENs reveal a better long-term outcome with recurrences observed in patients with large tumors, ≥5.0 cm, or with aggressive grade 3 tumors.158,170
TSC is a rare inherited autosomal dominant syndrome caused by mutations in 2 tumor suppressor genes, TSC1 mapped to chromosome 9q34 and TSC2 mapped to chromosome 16p13.3, encoding for the proteins hamartin and tuberin, respectively.133,179,180 The protein tuberin-hamartin complex involves multiple intracellular signaling pathways regulating both cell growth and proliferation.179,181 Patients with TSC are characterized mainly by multiorgans hamartomatous lesions, disabling neurologic features (epilepsy, mental retardation) and cutaneous lesions, typically facial angiofibroma, hypomelanocytic macules and ungula fibromas.181,182 Although there is limited data linking TSC to an increased risk of panNENs, both functioning (gastrinomas and insulinomas) and N-F tumors have been reported in patients with this syndrome, especially those with TSC2 mutation.183–188 Potential malignant behavior has been documented in rare cases.189,190 Consequently, careful clinical surveillance and appropriate surgical treatment should be considered on a case-to-case basis.
GCHN is a rare inherited recessive syndrome with an estimated ten cases documented in literature.191,192 Germline mutation of the GCGR gene, located on chromosome 17q25, has been identified in half of these syndromic patients giving a potential insight into the pathophysiology of this uncommon disorder. It is believed that GCGR mutation alters its overall protein function and expression causing an abnormal feedback mechanism between glucagon signaling in the liver and the glucagon cells of the pancreas.191,193,194 This deficient communication pathway results in an increased glucagon serum level and multifocal pancreatic glucagon cell hyperplasia, microadenomas and macroadenomas.191,192 These pancreatic lesions show well-differentiated panNET morphology with occasional cystic changes and calcifications in larger tumors and positive expression for glucagon immunohistochemistry. Although most GCHN followed a benign course post partial pancreatectomy, metastatic lymph node disease has been reported.191
Poorly differentiated panNECs are rare and account for ∼2% to 3% of pancreatic neuroendocrine cancers.12,115,195 PanNECs have a slight male predominance with an incidence peak in the sixth to seventh decade and frequently involve the head of the pancreas. Their clinical presentation is very similar to exocrine pancreatic tumors and are related to their location, large size and both obstructive and somewhat invasive nature. As a result, postobstructive jaundice, back pain, and/or nonspecific abdominal complaints are the only signs and symptoms available to suspect the diagnosis.12,13,196 On histologic assessment, panNECs usually present with a nested, organoid, or solid growth-like pattern composed of highly atypical small to large polygonal cells with large vesicular nuclei and often prominent nucleoli. The small cell type has a more infiltrative growth pattern. The large cell type is more commonly observed, accounting for ∼60% of cases.12,197 Areas of geographic necrosis, vascular invasion, and mitoses are easily identifiable (Fig. 9). Both tumors are reminiscent of small and large cell carcinoma of the lungs. Because of its high-grade histologic features, immunohistochemical studies are needed to confirm the diagnosis. Like its well-differentiated counterpart, panNEC immunostains demonstrate neuroendocrine differentiation. The tumor cells should express diffuse or focal, sometimes only dot-like, synaptophysin staining in variable intensity. Chromogranin A, although a useful specific marker, can occasionally be negative. In addition, less specific markers such as CD56 and NSE, which are interpreted in conjunction with both synaptophysin and/or chromogranin A positivity, may or may not be expressed in the tumor, but are still helpful tools in the diagnosis of more difficult cases.12,13,196,197 On a morphologic standpoint, the distinction between panNET, well-differentiated (G3) and panNEC, poorly differentiated (G3), can be challenging. To facilitate the distinction, both p53 and Rb markers are good and reliable immunostains to use, which have been identified in 95% and 74% of panNECs, respectively. PanNEC is characterized by strong and diffuse p53 nuclear expression in at least >20% of the tumors, in addition to complete loss of Rb expression.16,26
By definition, panNECs are graded based on their proliferative activity evaluation as >20 mitoses per 10 high-power fields or ki-67 proliferation index >20%.10 Nevertheless, most panNECs are very mitotically active and cases with >40 to 50 mitoses per high-power fields or ki-67 proliferation index >50% are frequently observed.12,13,197
Targeted molecular sequencing of panNECs has identified somatic genetic alterations involving predominantly: TP53, KRAS, PIK3CA/PTEN, and BRAF.198,199 At a lesser frequency, other genes such as RB1, CDKN2A/p16, APC, FBXW7, WNT, BCL2, and CTNNB1 can be mutated.198 Molecular abnormalities encountered in panNETs (MEN1, DAXX, and ATRX) and ductal pancreatic adenocarcinoma (SMAD4/DPC4) are not common features of panNEC.200,201 TP53 is a well-known tumor suppressor gene with multiple functions including cell division, apoptosis, and DNA repair and its mutation has been documented in more than half of cases.198,200,201 TP53 mutation usually leads to nuclear accumulation of the protein characterized as strong nuclear staining seen on immunohistochemical studies. Few cases of nonsense mutation in the TP53 gene were identified resulting in the absence of protein accumulation objectified on immunohistochemical stains as complete absence of nuclear p53 labeling.200 Abnormal immunostaining pattern for p53 and the Rb indicates that inactivation of these 2 pathways is a central feature for panNEC development. Additional correlations suggest that loss of Rb protein is mutually exclusive with the loss of p16 protein, supporting the known relationship of Rb and CDKN2A/p16 pathways in cell cycle regulation.199,200 KRAS mutations, although mainly described in colorectal cancers, were documented in different proportions in panNECs ranging from 0% to 50% in some studies.198,200–203
Mixed ductal-neuroendocrine carcinomas are a rare and aggressive neoplasm accounting for <0.5% of all pancreatic ductal adenocarcinomas.10,204–206 More than 70% of these mixed cancers are located in the head of the pancreas and present with symptoms related to their mass effect, although one case of ZES and another with the WDHA syndrome have been reported.10,207–210 They are usually quite large at time of presentation, measuring 1.4 to 19.0 cm in largest diameter, with a mean of 7.0 cm.208 Both mixed components are confined to a solitary, well-demarcated, white-to-yellow mass with occasional hemorrhagic or necrotic foci. This tumor exhibits morphologic characteristics of non-neuroendocrine carcinoma, usually an adenocarcinoma, admixed with a neuroendocrine neoplasm. Histologically, 2 different architectural patterns are described. In the first one, malignant ductal and neuroendocrine cells are intertwined together to form glandular, trabecular and various architectures. In the other pattern, separate ductal and neuroendocrine components are combined to form one tumors (Fig. 10).208,211,212 Immunohistochemical makers are strongly recommended to highlight both cell populations. For a diagnosis of mixed ductal-neuroendocrine carcinoma to be rendered, it is recommended for each tumor cell-type to account for ≥30% of the overall tumor cell population.10,213 Normally, both tumors are graded as poorly differentiated high-grade neoplasms (G3); however, well-differentiated endocrine neoplasms, G1/G2, are possible.210,212–214
Despite few documented cases, this mixed tumor seems to have similar or slightly better prognosis than pure ductal pancreatic adenocarcinoma but worse prognosis than pure endocrine carcinoma, likely contributed by the ductal adenocarcinoma component.205,208,215–218
Despite the small number of cases, the prognosis of MANEC seems similar to that of pure acinar carcinoma. Patients with surgically resectable disease have a favorable prognosis with a 5-year survival of 30% to 50%.212,221,228,229 While patients with nonresectable malignancies usually do not survive beyond 5 years.221
PanNENs are a heterogenous group of tumors representing only 1% to 2% of all pancreatic cancers. They encompass tumors with a wide spectrum of potential pathologic behaviors. Their clinical presentation varies from nonspecific mass-related symptoms to hypersecretory state and inherited syndromes, making their identification a diagnostic challenge.
The new WHO 2017 classification categorized panNENs into 3 groups based predominantly on histopathologic criteria, including ki-67 proliferative index and mitotic index, in addition to diagnostic immunohistochemical markers to further stratify each tumors into their respective categories. The purpose of this new system is to provide strong diagnostic and prognostic tools to better assess clinical outcomes and to determine optimal therapeutic strategies and patient care.
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