The 2010 WHO classification of tumors of the digestive system grades all the neuroendocrine tumors into three categories, based on their degree of cellular differentiation (from well-differentiated "NET G1" through to poorly-differentiated "NET G3"). The NCCN recommends use of the same AJCC-UICC staging system as pancreatic adenocarcinoma. Using this scheme, the stage by stage outcomes for PanNETs are dissimilar to pancreatic exocrine cancers. A different TNM system for PanNETs has been proposed by The European Neuroendocrine Tumor Society.

CT-scans, MRIs, sonography (ultrasound), and endoscopy (including endoscopic ultrasound) are common diagnostic tools. CT-scans using contrast medium can detect 95 percent of tumors over 3 cm in size, but generally not tumors under 1 cm.

Advances in nuclear medicine imaging, also known as molecular imaging, has improved diagnostic and treatment paradigms in patients with neuroendocrine tumors. This is because of its ability to not only identify sites of disease but also characterize them. Neuronedocrine tumours express somatostatin receptors providing a unique target for imaging. Octreotide is a synthetic modifications of somatostatin with a longer half-life. OctreoScan, also called somatostatin receptor scintigraphy (SRS or SSRS), utilizes intravenously administered octreotide that is chemically bound to a radioactive substance, often indium-111, to detect larger lesions with tumor cells that are avid for octreotide.

Somatostatin receptor imaging can now be performed with positron emission tomography (PET) which offers higher resolution, three-dimensional and more rapid imaging. Gallium-68 receptor PET-CT is much more accurate than an OctreoScan.

Imaging with fluorine-18 fluorodeoxyglucose (FDG) PET may be valuable to image some neuroendocrine tumors. This scan is performed by injected radioactive sugar intravenously. Tumors that grow more quickly use more sugar. Using this scan, the aggressiveness of the tumor can be assessed.

The combination of somatostatin receptor and FDG PET imaging is able to quantify somatostatin receptor cell surface (SSTR) expression and glycolytic metabolism, respectively. The ability to perform this as a whole body study is highlighting the limitations of relying on histopathology obtained from a single site. This is enabling better selection of the most appropriate therapy for an individual patient.

In general, treatment for PanNET encompasses the same array of options as other neuroendocrine tumors, as discussed in that main article. However, there are some specific differences, which are discussed here.

In functioning PanNETs, octreotide is usually recommended prior to biopsy or surgery but is generally avoided in insulinomas to avoid profound hypoglycemia.

PanNETs in MEN1 are often multiple, and thus require different treatment and surveillance strategies.

Some PanNETs are more responsive to chemotherapy than are gastroenteric carcinoid tumors. Several agents have shown activity. In well differentiated PanNETs, chemotherapy is generally reserved for when there are no other treatment options. Combinations of several medicines have been used, such as doxorubicin with streptozocin and fluorouracil (5-FU) and capecitabine with temozolomide. Although marginally effective in well-differentiated PETs, cisplatin with etoposide has some activity in poorly differentiated neuroendocrine cancers (PDNECs), particularly if the PDNEC has an extremely high Ki-67 score of over 50%.

Several targeted therapy agents have been approved in PanNETs by the FDA based on improved progression-free survival (PFS):

- everolimus (Afinitor) is labeled for treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease. The safety and effectiveness of everolimus in carcinoid tumors have not been established.

- sunitinib (Sutent) is labeled for treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease. Sutent also has approval from the European Commission for the treatment of 'unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors with disease progression in adults'. A phase III study of sunitinib treatment in well differentiated pNET that had worsened within the past 12 months (either advanced or metastatic disease) showed that sunitinib treatment improved progression-free survival (11.4 months vs. 5.5 months), overall survival, and the objective response rate (9.3% vs. 0.0%) when compared with placebo.

Surgery, if feasible, is the only curative therapy. If the tumor has metastasized (most commonly, to the liver) and is considered incurable, there are some promising treatment modalities, such as radiolabeled octreotide (e.g. Lutetium (Lu) DOTA-octreotate) or the radiopharmaceutical 131I-mIBG (meta iodo benzyl guanidine) for arresting the growth of the tumors and prolonging survival in patients with liver metastases, though these are currently experimental.

Chemotherapy is of little benefit and is generally not indicated. Octreotide or Lanreotide (somatostatin analogues) may decrease the secretory activity of the carcinoid, and may also have an anti-proliferative effect. Interferon treatment is also effective, and usually combined with somatostatin analogues.

As the metastatic potential of a coincidental carcinoid is probably low, the current recommendation is for follow up in 3 months with CT or MRI, labs for tumor markers such as serotonin, and a history and physical, with annual physicals thereafter.

The diagnosis of urachal cancer can be difficult and usually requires a multidisciplinary approach. A calcification in the midline can be detected in some patients in abdominal imaging studies. A cystoscopy is helpful in most cases. For diagnosis evaluation of a tissue biopsy is needed, which is usually obtained by transurethral resection (TURBT). Measurement of serum concentrations of CEA, CA19-9 and CA125 can be helpful in monitoring urachal cancer

The main treatment modalities are surgery, embolization and radiotherapy.

Genetic changes are very high in SCLC and LCNEC, but usually low for TC, intermediate for AC.

The diagnosis of SCLC, TC and AC can be made by light microscopy without the need for special tests in most cases, but for LCNEC it is required to demonstrate NE differentiation by immunohistochemistry or electron microscopy.

Esthesioneuroblastoma is a slow developing but malignant tumor with high reoccurrence rates because of its anatomical position. The tumor composition, location and metastatic characteristics as well as the treatment plan determine prognosis. Common clinical classification systems for esthesioneuroblastoma include the Kadish classification and the Dulguerov classfictation. Histopathological characteristics on top of Kadish classification can further determine cancer prognosis. In severe, Kadish class C tumors, Haym's grades of pathology are important for prognosis. Patients with low grade Kadish class C tumors have a 10-year survival rate of 86 percent compared to patients with high grade class C tumors who have a survival rate of 28 percent. Surgically treated patients with high grade tumors are more likely to experience leptomeningeal metastases or involvement of the cerebral spinal fluid unlike patients with low grade tumors who usually only see local recurrence. Survival rates for treated esthesioneuroblastoma are best for surgery with radiotherapy (65%), then for radiotherapy and chemotherapy (51%), just surgery (48%), surgery, radiotherapy and chemotherapy (47) and finally just radiotherapy (37%). From the literature, radiotherapy and surgery seem to boast the best outcome for patients. However, it is important to understand that to some degree, prognosis is related to tumor severity. More progressed, higher grade tumors would result in chemotherapy or radiotherapy as the only treatment. It is no surprise that the prognosis would be worse in these cases.

Symptoms from secreted hormones may prompt measurement of the corresponding hormones in the blood or their associated urinary products, for initial diagnosis or to assess the interval change in the tumor. Secretory activity of the tumor cells is sometimes dissimilar to the tissue immunoreactivity to particular hormones.

Given the diverse secretory activity of NETs there are many other potential markers, but a limited panel is usually sufficient for clinical purposes. Aside from the hormones of secretory tumors, the most important markers are:

- chromogranin A (CgA), present in 99% of metastatic carcinoid tumors

- urine 5-hydroxyindoleacetic acid (5-HIAA)

- neuron-specific enolase (NSE, gamma-gamma dimer)

- synaptophysin (P38)

Newer markers include N-terminally truncated variant of Hsp70 is present in NETs but absent in normal pancreatic islets. High levels of CDX2, a homeobox gene product essential for intestinal development and differentiation, are seen in intestinal NETs. Neuroendocrine secretory protein-55, a member of the chromogranin family, is seen in pancreatic endocrine tumors but not intestinal NETs.

Urachal cancer usually is an adenocarcinoma (about 90%) mostly with mucinous/colloidal histology. The histology can be difficult to distinguish especially from colorectal cancer and primary adenocarcinoma of the urinary bladder. Immunohistochemistry in this situation is of little help with stains for betaCatenin and Cytokeratin 7 can be helpful. Other rare types include urothelial carcinoma, squamous cell carcinoma, neuroendocrine carcinoma and sarcoma.

Diagnostic systems in use are the Sheldon system based on proposals from Wheeler and Hill and Mostofi. Recent diagnostic classification schemes have been proposed by Herr et al and Gopalan et al. For non-adenocarcinoma urachal cancer a diagnostic classification scheme has been proposed by Paner et al.

Carcinoid Syndrome is multiple in 1/5 cases.

Incidence of Gastric Carcinoid is increased in Achlorhydria,Hashimoto's thyroiditis,Pernicious anemia.

Esthesioneuroblastoma can resemble small blue cell tumors like squamous cell carcinoma, sinonasal undifferentiated carcinoma, extranodal NK/T cell lymphoma, nasal type, rhabdomyosarcoma, Ewing/PNET, mucosal malignant melanoma and neuroendocrine carcinomas (NEC) that occur in the intranasal tract. Compared to other tumors in the region, esthesioneuroblastoma has the best prognosis, with an overall 5 year survival rate of 60-80%. Fewer than 700 cases have been documented in the United States alone. Esthesioneuroblastoma is characterized by neurofibrillary stroma and neurosecretary granules that are not seen concurrently by any other pathologies in the region. Histological tests such as keratin, CK5/6, S-100 protein or NSE can be run to further differentiate esthesioneuroblastoma from other tumors.

Because of the way familial polyposis develops, it is possible to have the genetic condition, and therefore be at risk, but have no polyps or issues so far. Therefore, an individual may be diagnosed "at risk of" FAP, and require routine monitoring, but not (yet) actually have FAP (i.e., carries a defective gene but as yet appears not to have any actual medical issue as a result of this). Clinical management can cover several areas:

- Identifying those individuals who could be at risk of FAP: usually from family medical history or genetic testing

- Diagnosis (confirming whether they have FAP)—this can be done either by genetic testing, which is definitive, or by visually checking the intestinal tract itself.

- Screening / monitoring programs involve visually examining the intestinal tract to check its healthy condition. It is undertaken as a routine matter every few years where there is cause for concern, when either (a) a genetic test has confirmed the risk or (b) a genetic test has not been undertaken for any reason so the actual risk is unknown. Screening and monitoring allows polyposis to be detected visually before it can become life-threatening.

- Treatment, typically surgery of some kind, is involved if polyposis has led to a large number of polyps, or a significant risk of cancer, or actual cancer.

It is important to exclude a tumor which is directly extending into the ear canal from the parotid salivary gland, especially when dealing with an adenoid cystic or mucoepidermoid carcinoma. This can be eliminated by clinical or imaging studies. Otherwise, the histologic differential diagnosis includes a ceruminous adenoma (a benign ceruminous gland tumor) or a neuroendocrine adenoma of the middle ear (middle ear adenoma).

The MACIS system of estimating the prognosis of papillary thyroid cancer was developed by Clive S. Grant at the Mayo Clinic, and was based on careful evaluation of a large group of patients. It is probably the most reliable staging method available.

It assigns scores to the main factors involved, and uses the sum of this score to calculate the prognosis:

Most patients fall into the low-risk category (MACIS score less than 6.0) and are cured of the cancer at the time of surgery.

Children with multiple lung metastases and/or a miliary aspect still have an excellent long-term prognosis if given adequate treatment.

Monitoring involves the provision of outpatient colonoscopy, and occasionally upper gastric tract esophagogastroduodenoscopy (EGD, to search for premalignant gastric or duodenal tumors), typically once every 1–3 years, and/or a genetic blood test to definitively confirm or deny susceptibility. A small number of polyps can often be excised (removed) during the procedure, if found, but if there are more severe signs or numbers, in patient surgery may be required.

NCBI states that when an individual is identified as having FAP, or the mutations resulting in FAP: "It is appropriate to evaluate the parents of an affected individual (a) with molecular genetic testing of APC if the disease-causing mutation is known in the proband [person first identified with the condition] or (b) for clinical manifestations of APC-associated polyposis conditions".

Because of its rarity, there have been no randomized clinical trials of treatment of GCCL, and all information available derives from small retrospective institutional series or multicenter metadata.

Antibodies may be used to determine the expression of protein markers on the surface of cancer cells. Often the expression of these antigens is similar to the tissue that the cancer grew from, so immunohistochemical testing sometimes helps to identify the source of the cancer. Individual tests often do not provide definitive answers, but sometimes patterns may be observed, suggesting a particular site of origin (e.g. lung, colon, etc.). Immunohistochemical testing suggests a single source of cancer origin in about one in four cases of CUP. However, there is a lack of definitive research data showing that treatment guided by information from immunohistochemical testing improves outcomes or long-term prognosis.

Giant-cell lung cancers have long been considered to be exceptionally aggressive malignancies that grow very rapidly and have a very poor prognosis.

Many small series have suggested that the prognosis of lung tumors with giant cells is worse than that of most other forms of non-small-cell lung cancer (NSCLC), including squamous cell carcinoma, and spindle cell carcinoma.

The overall five-year survival rate in GCCL varies between studies but is generally considered to be very low. The (US) Armed Forces Institute of Pathology has reported a figure of 10%, and in a study examining over 150,000 lung cancer cases, a figure of 11.8% was given. However, in the latter report the 11.8% figure was based on data that included spindle cell carcinoma, a variant which is generally considered to have a less dismal prognosis than GCCL. Therefore, the likely survival of "pure" GCCL is probably lower than the stated figure.

In the large 1995 database review by Travis and colleagues, giant-cell carcinoma has the third-worst prognosis among 18 histological forms of lung cancer. (Only small-cell carcinoma and large-cell carcinoma had shorter average survival.)

Most GCCL have already grown and invaded locally and/or regionally, and/or have already metastasized distantly, and are inoperable, at the time of diagnosis.

From a pathology perspective, several tumors need to be considered in the differential diagnosis, including paraganglioma, ceruminous adenoma, metastatic adenocarcinoma, and meningioma.

Small carcinoids (<2 cm) without features of malignancy may be treated by appendectomy if complete removal is possible. Other carcinoids and adenocarcinomas may require right hemicolectomy. Note: the term "carcinoids" is outdated: these tumors are now more accurately called "neuroendocrine tumors." For more information, see "appendiceal neuroendocrine tumors."

Pseudomyxoma peritonei treatment includes cytoreductive surgery which includes the removal of visible tumor and affected essential organs within the abdomen and pelvis. The peritoneal cavity is infused with heated chemotherapy known as HIPEC in an attempt to eradicate residual disease. The surgery may or may not be preceded or followed with intravenous chemotherapy or HIPEC.

GCCs have an aggressive course compared to other appendiceal neuroendocrine tumours.

Based on overall cancer staging into stages I to IV, papillary thyroid cancer has a 5-year survival rate of 100 percent for stages I and II, 93 percent for stage III and 51 percent for stage IV.

Patients treated with complete surgical excision can expect an excellent long term outcome without any problems. Recurrences may be seen in tumors which are incompletely excised.