Well-differentiated Endocrine Tumors Research Articles

Criteria for Malignancy in Gastrointestinal Endocrine Tumors

In contrast with the large amount of data generated from endocrine tumors of the pancreas, sparse and mostly unconfirmed data are available on the criteria for the assessment of malignancy risk and patient outcome in endocrine tumors of the gastrointestinal tract. In these conditions the 2000 WHO classification with its standardized scheme of pathologic report constitutes a framework facilitating the assessment of tumor malignancy and has been regarded as useful for clinical purposes, providing the basis for proper management of the patients and for the design of treatment protocols. The classification is based on a combination of pathological and clinical features with parameters specific for each organ in which the endocrine tumors originate. Three main categories, one further subdivided into two subgroups, are considered: (1) well-differentiated endocrine tumors, further subdivided into tumors with benign and with uncertain behavior; (2) well-differentiated endocrine carcinomas, low grade; and (3) poorly differentiated endocrine carcinomas, high grade. In this review the differential tumor characteristics between the different categories are summarized. Moreover, the relevance of additional features with respect to tumor prognostication, chiefly the Ki-67 proliferation index and malignancy-associated genetic changes, is discussed with emphasis on the discrepancies emerging between tumors of foregut and of midgut origin.

Insulinoma With Slow Growth

The organic hyperinsulinism was detected in a 52 year-old man but with no localization of pancreatic functional endocrine tumor using the standard noninvasive imaging studies (ultrasonography, computed tomography). An insulinoma is a rare tumor, typically less than 2 cm in diameter. The period of 15 years with symptoms of hypoglycaemia was passed before the tumor was evident with imaging studies (endoscopic ultrasound and abdominal computed tomography). The operative and pathologic findings confirm the diagnosis of insulinoma as well-differentiated functional endocrine tumor with benign biologic behaviour.

Clinical utility of telomerase for the diagnosis of malignant well‐differentiated endocrine tumours

The distinction between benign and malignant well-differentiated endocrine tumours is hard to achieve. The aim of the present study was to determine whether detection of telomerase or quantification of human telomerase reverse transcriptase protein subunit (hTERT) differ between benign and malignant endocrine tumours. This retrospective study investigated 31 well-differentiated primary endocrine tumours. Based on clinical and histopathological criteria, tumours were categorized with the most recent WHO classification as 'benign' (n = 14), 'uncertain' (n = 5) or 'malignant' (n = 12) with (n = 7) or without (n = 5) metastasis after a mean follow-up of 40.4 +/- 25.8 months (4-122 months). All these tumours were assayed for telomerase activity and hTERT mRNA expression [real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR)]. Telomerase activity was detected in 7 malignant and metastatic tumours, in 1 malignant tumour without metastases, in 1 uncertain tumour and in 1 benign tumour. hTERT mRNA levels were significantly higher in malignant endocrine tumours with or without metastases (P = 0.001) when compared to benign tumours. The negative predictive value of hTERT mRNA quantification for the diagnosis of malignancy was 88.9%, whereas the positive predictive value was 68.7%. The presence of telomerase activity within the primary endocrine tumour might indicate a malignant tumour and might suggest the need for an attentive search for concomitant metastases. Quantification of hTERT mRNA could be used in clinical practice to exclude malignancy in most endocrine tumours.

A clear cell malignant gastrinoma of the pancreas with cytoplasmic accumulation of lipid droplets

Sir: Well-differentiated endocrine tumours of the pancreas are usually diagnosed without difficulty by the presence of small eosinophilic cells with a characteristic disposition in cordons, solid nests, tubules and acini separated by a highly vascularised stroma. Clear cell endocrine tumours are rare in the pancreas in the absence of von Hippel–Lindau (VHL) disease, and changes resulting in clear cell appearance are poorly described. We report here the case of a sporadic, malignant clear cell gastrinoma of the pancreas with multiple hepatic metastasis and describe its specific imaging and histological appearances. A 48-year-old woman with a Zollinger–Ellison syndrome, evidenced by epigastric pain, diarrhea, weight loss and presence of multiple gastroduodenal ulcers on endoscopy, was admitted to Beaujon Hospital. Laboratory tests revealed elevated levels of circulating chromogranin (5,933

Traitement chirurgical des tumeurs endocrines gastro-entéro-pancréatiques: 2. Traitement des métastases hépatiques

The development of hepatic metastases (HM) marks a turning point in the evolution and prognosis of well-differentiated endocrine tumors (ET). Management is usually multicisciplinary (chemotherapy, arterial chemo-embolization, percutaneous ablation, somatostatin analogs, biotherapy, and surgery). A thorough pre-operative work-up is neecessary to exclude extrahepatic disease and to detect tiny HM's. Complete resection (R0) is the only curative treatment for well-differentiated ET with HM. The type of resection is specific to each case and may range from wedge resection of a metastasis to complex hepatectomy with simultaneous resection of the primary ET. Cytoreductive surgery may be indicated for palliation when medical therapy fails to control endocrine symptoms. Operative mortality is low (0-6%) and global survival is 60-70% after R) resection of HM of well-differentiated ET's. After resection of HM involving only one hepatic lobe, 5 year survival is better than 90%. When HM are multiple, bilobar and synchronous, the prognosis is very poor -only 10% of such patients can have a complete resection and this often requires a long prologue of ancillary procedures (chemotherapy, chemoembolization, portal vein ligation, percutaneous ablation). Hepatic transplantation (HT) has only a limited rôle in the treatment of HM for ET ; mortality is high when HT is associated with large and complex resections, i.e. pancreaticoduodenectomy. Although there is no consensus in the literature, HT should be limited to the most optimal cases (young, good general health, well-differentiated tumor, slow evolution, complete resection of the primary tumor, and unresectable liver metastases). Global survival for HT in patients with ET is 60% at 2 years, 47% at 5 years; tumor-free survival at 5 years is 24%. HT for HM has better survival results for ET's of intestinal origin (carcinoids) than for duodenopancreatic ET's.

Pathological features and their prognostic implications in colorectal endocrine cell tumours: a long-term follow-up study

Long-term follow-up studies of colorectal endocrine cell tumours (CRECTs) are rare. Our aim was to correlate pathological features with metastatic potential and long-term survival of CRECTs. Pathological features of 35 CRECTs were reviewed. Features assessed were the tumour size, local and angio-invasion, growth pattern, cyto-nuclear morphology, mitotic count, mucin production and proliferative activity. CRECTs were also re-classified according to the World Health Organization (WHO) 2000 criteria. The follow-ups ranging from 60 to 132 months was obtained from Singapore National Cancer Registry data. There were five metastatic and 30 non-metastatic tumours. Three of five metastatic tumours resulted in death within 1 year of diagnosis. Features exclusively seen in these three tumours were large size (25mm or more), mitoses > 6/10 high power fields with abnormal forms necrosis and large cell morphology. The features which correlated significantly with metastases were size, local and angioinvasion, primitive growth pattern, coarse chromatin and mitotic count (p < 0.0005), large cells and prominent nucleoli (p = 0.017), MIB1 proliferative index (p = 0.001) and abnormal mitoses and necrosis (p = 0.02). Thirty tumours were reclassified as well-differentiated endocrine cell tumours (WETs), three as well-differentiated endocrine cell carcinomas (WECs) and two were large cell neuroendocrine cell carcinomas (LECs) according to WHO criteria. One of the WECs and both LECs resulted in death. All patients whose tumour was 25 mm or more, showing mitoses of more than 6 per 10 high power fields, with abnormal forms, necrosis and large cell morphology, died of the disease. Size, invasion, presence of discernible mitoses, coarse chromatin, 'primitive' growth pattern and MIB1 index of 4% or more were associated with metastases. LECs are rare but aggressive tumours resulting in early death. All WECs do not behave in the same fashion.

Traitement chirurgical des tumeurs endocrines gastro-entéro-pancréatiques

Endocrine tumors (ET) of the digestive tract (formerly called neuroendocrine tumors) are rare. They are classified into two principal types: gastrointestinal ET's (formerly called carcinoid tumors) which are the most common, and pancreaticoduodenal ET's. Functioning ET's secrete polypeptide hormones which cause characteristic hormonal syndromes. The management of ET is multidisciplinary. Poorly-differentiated ET's have a poor prognosis and are treated by chemotherapy. Surgical excision is the only curative treatment of well-differentiated ET's. The surgical goals are to: 1. prolong survival by resecting the primary tumor and any nodal or hepatic metastases. 2. control the symptoms related to hormonal secretion. 3. prevent or treat local complications. The most common sites of gastrointestinal ET's ( carcinoids) are the appendix and the rectum ; these are often small (<1 cm.), benign, and discovered fortuitously at the time of appendectomy or colonoscopic removal. Ileal ET's, even if small, are malignant, frequently multiple, and compicated in 30-50% of cases by bowel obstruction, mesenteric invasion, or bleeding. The carcinoid syndrome (consisting of abdominal pain, flushing, diarrhea, hypertension, bronchospasm, and right sided cardiac vegetations) is caused by the hypersecretion of serotonin into the systemic circulation; it occurs in 10% of cases and is usually associated with hepatic metastases. More than half of the cases of pancreatic ET are non-functional. They are usually malignant and of advanced stage at diagnosis presenting as a palpable or obstructing mass or as liver metastases. Insulinoma and gastrinoma (cause of the Zollinger-Ellison syndrome) are the most common functional ET's. 80% are sporadic; in these cases, tumor size, location, and malignant potential determine the type of resection which may vary from a simple enucleation to a formal pancreatectomy. In 10-20% of cases, pancreaticoduodenal ET presents in the setting of multiple endocrine neoplasia (NEM type I), an autosomal-dominant genetic disease with multifocal endocrine involvement of the pituitary, parathyroid, pancreas, and adrenal glands. For insulinoma with NEM-I, enucleation of lesions in the pancreatic head plus a caudal pancreatectomy is the most appropriate procedure. For gastrinoma with NEM-I, the benefit of surgical resection for tumors less than 2-3 cm. in sizeis not clear. The lesions are frequently small, multiple, and widespread and recurrence is frequent after excision. The long-term prognosis is nevertheless fairly good. But the eventual development of liver metastases which are the most common cause of mortality still argues for an aggressive surgical approach in the early stages of the disease.

Carcinoid of the ampulla of Vater

Endocrine neoplasms only rarely occur at the ampulla of Vater, comprising mostly carcinoids and malignant carcinoids, as well as few cases of poorly differentiated endocrine carcinomas (small cell carcinomas). Only 105 cases are reported in the literature, most as single case reports. For many years, the neoplasms of the disseminated neuroendocrine cell system of the gastrointestinal tract have been subsumed as 'carcinoids'. Instead, in the latest World Health Organization (WHO) classification published in 2000, it is recommended to distinguish between (i) well-differentiated endocrine tumors (carcinoids); (ii) well-differentiated endocrine carcinomas (malignant carcinoids); and (iii) poorly differentiated endocrine carcinomas (small cell carcinomas). Patients with carcinoid tumors of the ampulla of Vater are very often free of clinical and laboratory findings that belong to the carcinoid syndrome. Approximately 26% of all patients with carcinoid tumor reported in the literature had neurofibromatosis. Besides endoscopic retrograde cholangiopancreatography, endosonography, computed tomography or magnetic resonance imaging may complete the staging approach of this tumor. The Kausch-Whipple procedure or pylorus-preserving pancreaticoduodenectomy is considered the treatment of choice for ampullary, well-differentiated carcinoids >2.0 cm and for ampullary neuroendocrine carcinomas. However, it should be considered that long-term survival of patients with ampullary carcinoids is also reported after local tumor excision (5-year survival rate of 90%). The dilemma is that the differentiation of neuroendocrine tumors cannot be assessed intraoperatively in most cases. Therefore, considering that the 5-year survival rate in patients with neuroendocrine carcinomas of the ampulla of Vater is very low without radical resection, neuroendocrine tumors of the ampulla of Vater without definite histological differentiation should undergo extended surgery.

Large-cell neuroendocrine carcinoma of the major duodenal papilla: case report

For many years, neoplasms of the disseminated neuroendocrine cell system of the GI tract have been subsumed as “carcinoids.” However, because these tumors have a broad morphologic and biologic spectrum, this is no longer adequate.1 Instead, the latest World Health Organization (WHO) classification (2000) recommends that these tumors be differentiated into 3 types: (1) well-differentiated endocrine tumor (carcinoid), (2) well-differentiated endocrine carcinoma (malignant carcinoid), and (3) poorly differentiated endocrine carcinoma (small-cell carcinoma).

Primary Mixed Adenocarcinoma and Small Cell Carcinoma of the Appendix

Appendiceal carcinoids range from well-differentiated endocrine tumor to well-differentiated endocrine carcinoma, while poorly differentiated (small cell) carcinoma has not been described in this site. We report herein a case of mixed intestinal-type adenocarcinoma associated with a small cell carcinoma arisen in a 35-year-old woman and clinically presenting as an appendiceal abscess. The resected tumor histologically appeared as a biphasic lesion composed of a nonmucinous adenocarcinoma closely juxtaposed with a poorly differentiated (small cell) endocrine carcinoma. The subsequent right hemicolectomy was unremarkable, but one pericolic lymph node showed a metastatic deposit consisting of the adenocarcinoma only. The patient thus underwent a chemotherapeutic protocol for colorectal cancer, and she is alive and well at the 65-month follow-up. Immunohistochemically, the adenocarcinoma strongly stained for cytokeratin 20 and carcinoembryonic antigen, while the endocrine component displayed a dot-like positivity for pan-cytokeratins and chromogranin. Of note, both components did not stain with CDX2 and p53. At genotypic analysis by microsatellite instability, both components shared many microsatellite alterations as well as a normal p53 gene setup, although small cell carcinoma harbored additional alterations. Clinical and molecular findings led us to consider this lesion as a clonal tumor in which the endocrine component seems to derive from a progressive differentiation of the adenocarcinoma following a glandular-to-endocrine sequence.

CDX2 as a marker of intestinal EC-cells and related well-differentiated endocrine tumors

Gastroenteropancreatic (GEP) endocrine tumors (ETs) are neoplasms showing different hormonal profiles and different clinical and prognostic features, which depend consistently on the site of origin. Histological features and general endocrine markers do not differentiate tumors in relation to their location, making it difficult to establish the site of origin of a GEP ET that has metastasized to the liver or lymph nodes. A site-specific marker would be particularly useful in the examination of small specimens where there is not sufficient material for an extensive study of the hormonal expression. CDX2 is a transcription factor that has been recently proposed as a marker of intestinal adenocarcinomas. Our aim was to evaluate the immunohistochemical expression of CDX2 in normal tissues and in 184 formalin-fixed and paraffin-embedded ETs to verify whether it could be used to identify intestinal ETs with a high degree of sensitivity and specificity. Of these cases, 154 were primary tumors (99 GEP and 55 non-GEP tumors), 101 were well-differentiated endocrine tumors, and 53 were poorly differentiated endocrine carcinomas (PDECs). Of the cases, 30 were metastases from differently located ETs. Nuclear CDX2 immunoreactivity was found in all EC-cells (serotonin-producing cells), in about 10% of G-cells (gastrin-producing cells), in about 30% of GIP-cells (gastric inhibitory peptide cells) and in a few motilin-positive cells of the normal intestinal mucosa, while other gastrointestinal endocrine cell types were CDX2 negative. All midgut EC-cell tumors, their metastases, and two of three pancreatic EC-cell ETs were diffusely and intensely CDX2 positive. The other GEP ETs, their metastases, as well as the non-GEP ETs, were all CDX2 negative, with the exception of four PDECs, five gastrinomas and one pheochromocytoma, which were only focally positive. We conclude that CDX2 may be considered a sensitive and specific marker of midgut EC-cells and EC-cell tumors, and its expression may be useful in the diagnosis of metastases from occult ETs.

Atypical endoscopic features of rectal carcinoids.

It is not normally difficult to diagnose carcinoid tumors (well-differentiated endocrine neoplasms) of the rectum endoscopically, as they usually have a characteristic appearance. However, little is known about the atypical endoscopic findings in some rectal carcinoids and the present study was performed to analyze these. The endoscopic findings in 67 consecutive patients with rectal carcinoids (37 men, 30 women; age range 23 - 76) were analyzed retrospectively. Tumor size ranged from 2 mm to 30 mm (average 7.4 mm). Of the 67 patients, 52 (78 %) displayed the characteristic endoscopic findings of smooth, round, sessile elevations covered with normal-appearing or yellow-discolored mucosa; in 15 (22 %) there were one or more atypical endoscopic findings. These included a semipedunculated appearance (n = 6), hyperemia (n = 5), a central depression (n = 6), erosion (n = 5), and ulceration (n = 4). Atypical findings were noted in none of 20 carcinoids &lambda< 5 mm in diameter; in six (20 %) of the 30 carcinoids between 5 mm and 9 mm; in six (43 %) of the 14 carcinoids between 10 mm and 19 mm; and in three (100 %) of the three carcinoids >/= 20 mm in diameter ( P < 0.001). Invasion into the muscularis propria or metastasis to the liver or lymph nodes occurred in three of the four patients with ulceration, but it was confirmed in only one of the 63 patients without ulceration ( P < 0.001). Atypical endoscopic appearances of rectal carcinoids are observed more frequently as the size of the tumor increases and a finding of ulceration may have a prognostic value.

Different molecular profiles characterize well-differentiated endocrine tumors and poorly differentiated endocrine carcinomas of the gastroenteropancreatic tract.

The molecular pathogenesis of gastroenteropancreatic endocrine tumors (ETs) is still largely unknown. The purpose of this work was a molecular characterization of 38 gastroenteropancreatic ETs with respect to the primary site and to the morphofunctional profile, pointing out useful diagnostic or prognostic molecular markers. Twenty-four well-differentiated ETs or carcinomas (WDET/Cs; 11 pancreatic, 3 gastric, and 10 intestinal) and 14 poorly differentiated endocrine carcinomas (1 pancreatic, 6 gastric, and 7 colorectal) were microallelotyped using 38 polymorphic microsatellite markers covering chromosomes 1, 3, 5q, 6, 11, 17, and 18. Regardless of the primary site, a significantly higher percentage of allelic imbalances (AIs) was observed in poorly differentiated endocrine carcinomas than in WDET/Cs (P = 0.012), except for 3 of 8 nonfunctioning pancreatic endocrine tumors and 1 colorectal WDEC, exhibiting multiple AIs on chromosomes 1, 3, 6, and 11. A strong positive correlation between AI percentage and Ki-67 proliferation index was detected considering both the whole series of ETs (P = 0.004) and the group of WDET/Cs alone (P = 0.011). The survival analysis showed a positive correlation between low percentage of AI and longer survival (P = 0.01). No recurrent AIs at specific chromosomal regions were identifiable with respect to the primary site. The malignant progression of endocrine tumors seems to be associated with complex allelotypes and chromosomal instability. Although no specific molecular markers of malignancy can be defined with certainty, the ploidy status and the degree of chromosomal derangements appear to be the most informative genetic factors with prognostic significance.

Liver resection (and associated extrahepatic resections) for metastatic well-differentiated endocrine tumors: A 15-year single center prospective study

Background. The timing and benefits of hepatectomy remain controversial for metastatic well-differentiated endocrine neoplasms, which are generally considered slow growth tumors. However, surveillance alone yields only a 22% 5-year survival when metastases occur. The aim of this study was to determine the results of hepatic and extra hepatic resections and to clarify the indications of surgery. Methods. To define the role of hepatic resection, a database regrouping all patients (n = 47) who underwent hepatectomy with curative intent (R0 status) for well-differentiated endocrine neoplasms in the Gustave-Roussy Institute was constructed in 1984. New prognostic factors such as tumor growth and liver tumor mitotic index were studied. Median follow-up was 62 months. Results. Hepatectomy was associated with extrahepatic tumor resection in 77% of the patients (primary tumor in 51%, lymph nodes in 21%, peritoneal carcinomatosis in 25%, and other in 6%). Resection was curative (R0) only in 53% of the patients, despite removing at least 97% of the tumor in each patient. Mortality was 5%, and morbidity was 45%. Median survival was 91 months, 5-year and 10-year overall survival rates were 71% and 35%, respectively. Liver recurrence rate was 75% at 10 years. No prognostic factor was correlated with overall survival in this population in which at least 97% of the tumor load was resected. The completeness of surgery, the presence of bilateral liver metastases, the number of liver metastases (>10) and a primary tumor from pancreatic origin were all significantly correlated with the disease-free survival. Preoperative tumor growth rate, mitotic index, and Ki67 expression were not predictive of prognosis. No significant prognostic factors could be found by the comparison of the patients who did and did not recur during the 3 years after hepatectomy. Conclusion. Hepatectomy for liver metastases from well-differentiated endocrine neoplasms is indicated when all visible intra- and extra hepatic lesions can be resected safely. The number, size, and localization of the tumor sites are less important than performing a complete (or near-complete) resection. (Surgery 2003;133:375-82.)

Ghrelin expression in gut endocrine growths.

We aimed to assess the occurrence of ghrelin, a new gut hormone, in endocrine growths of the stomach. In addition, since ghrelin has been detected in other gut derivatives during adult and/or fetal life, we also studied endocrine tumours of the pancreas, intestine and lung. A specific serum generated against amino acids 13-28 of ghrelin was tested on 16 specimens of gastric mucosa with endocrine cell hyperplasia and on 75 endocrine tumours. Ghrelin-immunoreactive cells were moderately represented in normal, atrophic or hypertrophic gastric mucosa, as a rule with no obvious hyperplastic changes even in the presence of concurrent, prominent enterochromaffin-like cell hyperplasia associated with hypergastrinemia. Ghrelin cells were also found in tumour cell fractions of well-differentiated gastric (25 of 33, 76%), pancreatic (6 of 15, 40%) and pulmonary (4 of 8) endocrine tumours. No ghrelin immunoreactivity was detected in 14 intestinal tumours and in five poorly differentiated endocrine carcinomas of the stomach or pancreas. We conclude that ghrelin cells may take part in gut endocrine growths, with special reference to well-differentiated endocrine tumours of the stomach, independently from associated signs of endocrine hyperfunction.

Claudin expression in rectal well-differentiated endocrine neoplasms (carcinoid tumors)

Claudins are the structures and functional components of tight junctions and have crucial roles in the maintenance of cell polarity, cellular arrangement, adhesion and paracellular transport. Various claudins are expressed in different epithelial cells and most tissues express multiple claudin proteins. The altered expression of claudins has been reported in various human carcinomas, but their expression in rectal well-differentiated endocrine neoplasms (carcinoid tumors), the most common endocrine tumors in the gastrointestinal tract, has yet to be examined. The expression of claudins-2, -3 and -4 in 16 rectal well-differentiated endocrine neoplasms was studied by immunohistochemical methods, and compared with their expression patterns in endocrine tumors of the pancreas and lung. According to previous reports, pancreatic endocrine tumors were positive for claudin-3 and negative for claudins-2 and -4, and a majority of lung carcinoid tumors showed no immunoreactivity to claudins-2, -3 and -4. However, our immunohistochemical study revealed that the rectal well-differentiated endocrine neoplasms showed diffuse positive immunoreactivity to claudins-2, -3 and -4. These results indicate that claudin expression depends on the site of origin of endocrine tumors. In addition, claudin-3 and -4 expression in rectal well-differentiated endocrine neoplasms suggests the possibility of a new therapeutic strategy. Claudins-3 and -4 are receptors for the cytotoxic Clostridium perfringens enterotoxin. This enterotoxin rapidly and specifically lyses cells expressing claudins-3 and -4 and has a potential application in cancer therapeutics. Accordingly, this enterotoxin may be applicable for the treatment of rectal well-differentiated endocrine neoplasms in the future in order to prevent unexpected metastatic recurrences after tumor resections, because these neoplasms have a relatively high incidence of metastases despite their small size.

The Pathology of the Gastrointestinal Endocrine System

Among endocrine tumors occurring in the gastrointestinal tract, midgut argentaffin EC cell carcinoids, gastric argyrophil ECL cell carcinoids, duodenal gastrin cell tumors, and rectal trabecular L cell carcinoids (in order of decreasing frequency) are those occurring more frequently. Together, they account for more than 80% of such tumors. Duodenal somatostatin cell tumors, gangliocytic paragangliomas, and differentiated neuroendocrine carcinomas are also well-defined tumor entities. The carcinoid syndrome, either classical, with intermittent flushing, hypotension, and diarrhea, or atypical, with persistent histamine-type red flushing, bronchospasm, and no diarrhea, and Zollinger-Ellison syndrome, with severe peptide ulcer disease, are the only hyperfunctional syndromes consistently found in association with these tumors. The carcinoid syndrome occurs in about 10% of gastrointestinal carcinoids, usually in their advanced, metastatic stage. The Zollinger-Ellison syndrome occurs in association with about 40% of intestinal gastrin cell tumors, including small intramural growths. Tumor prognosis depends on the mode and site of presentation, histology, cell type(s), size, level of invasion, metastases (especially distant metastases), and associated clinical syndrome or background disease. Hormones, trophic factors, inherited genetic traits, somatic mutations, and some chronic inflammatory processes are pathogenetically important in a large proportion of cases.