Rectal NETs

Introduction of Rectal NETs
The gastrointestinal tract is, on embryological basis, divided into fore-, mid- and hindgut. The latter region includes the middle part of colon transversum and distally. Hindgut contains neuroendocrine tumors (NETs), where rectal carcinoids represent the vast majority and the following information will mainly focus on them. Rectal carcinoids are divided to well-differentiated NETs (WD-NETs) and poorly differentiated endocrine carcinomas (PDECs).

Epidemiology of Rectal NETs
According to the Surveillance, Epidemiology, and End Results data of the National Cancer Institute at the United States of America, rectal NETs are the second most common NETs and are surpassed in prevalence only by the small bowel NETs. Rectal NETs represent approx. 15% of all NETs and around 30% of all gastrointestinal NETs with an incidence rate of roughly 1 case among 100.000 inhabitants/year. Despite this relative high incidence of NETs in the rectum, compared with other sites, these lesions comprise only 1–2% of all rectal tumors. In large series no significant specific gender predominance has been found (male:female crude and corrected ratios of 1.07 and 1.13, respectively). Substantial racial differences have been reported with a black:white ratio of 2.30 and Asian:non Asian ratio of almost 5.0. The average age at primary diagnosis is of around 52 yrs. The age range reported spans between 14-94 yrs.

Symptoms of Rectal NETs
Rectal carcinoids are asymptomatic in almost 50% of the cases. When symptoms are present they manifestate as haematochezia, constipation, diarrhoea, rectal pain, and weight loss. Rare cases have been described to be accompanied by the typical carcinoid- or the somatostatin-syndrome. Ectopic hormone production causing Cushing syndrome or acromegaly has also been described.

Diagnosis of Rectal NETs
Rectal NETs are frequently diagnosed as an incidental finding at routine endoscopy. Macroscopically they usually appear as solitary, smooth, submucosal nodulus or as mucosal/submucosal thickening. A minority of them can be accompanied by a central mucosa depression or ulceration.

Histopathology of Rectal NETs
I - Well differentiated tumors
Two types of WD-NETs occur: the enterochromaffin- (EC-) cell type and the L-cell type. The former type is serotonin-producing with similar growth patterns as seen in midgut carcinoid. These tumors show generally strong chromogranin A (CgA) and serotonin immunoreactivity. EC-cell type NETs comprise about 20-30% of all rectal WD-NETs. The L-cell type displays peptide tyrosine tyrosine/pancreatic polypeptide (PYY/PP) and/or glucagon-like peptide (GLP) immunoreactivity. In most L-cell type tumors a ribbon-like growth pattern predominates but tubuloacinar and irregular trabecular patterns may also be seen. In these tumors the intensity of CgA immunoreactivity is usually weak or even absent, whereas synaptophysin immunoreactivity is more apparent. L-cell type tumors represent the majority of rectal NETs (around 70-80%). Rarely, rectal WD-NETs have been reported to contain somatostatin immunoreactive cells. Another marker used for the identification of rectal WD-NETs is the prostatic acid phosphatase, a finding that can be explained due to the common embryological origin of the prostate and the rectum from the cloaca. All the above tumors have usually a Ki67 proliferation index of less than 2% with rare mitoses.

A rectal WD-NET of EC-type showing insular tumour growth. Virtually all tumour cells are chromogranin A immunoreactive. Multiple tumour cells show serotonin immunoreactivity of varying intensity.

A rectal WD-NET of EC-type showing insular tumour growth. Virtually all tumour cells are chromogranin A immunoreactive. Multiple tumour cells show serotonin immunoreactivity of varying intensity
A rectal WD-NET of L-cell type with ribbon-like growth pattern displaying numerous GLP-1 immunoreactive cells. Few Ki67 immunoreactive nuclei are seen.

A rectal WD-NET of L-cell type with ribbon-like growth pattern displaying numerous GLP-1 immunoreactive cells. Few Ki67 immunoreactive nuclei are seen.

II - Poorly differentiated endocrine carcinomas
The PDECs can be of small-cell (SC) and large-cell (LC) type and they are identical to those in lung. Sometimes an overlying adenoma or an adjacent adenocarcinoma is related to SC-PDECs. They may lack CgA immunoreactivity which denotes loss of differentiation of the tumour but they usually express synaptophysin. The relative incidence of the Ki67 proliferation index is over 20% (often over 50%) and the number of mitoses can exceed 20 per 10 high power field (HPF). These high mitotic and Ki67 indexes are in concordance with their malignant potential.

A SC-PDEC with an overlying adenoma (haematoxylin-eosin staining). The vast majority of the tumour cells nuclei are Ki67 immunoreactive.

A SC-PDEC with an overlying adenoma (haematoxylin-eosin staining). The vast majority of the tumour cells nuclei are Ki67 immunoreactive.

Radiology and nuclear imaging of Rectal NETs
Endoscopic U/S is the cornerstone of the radiological investigations used during the assessment of the rectal carcinoids. Transabdominal U/S, CT, MRI, octreoscan, as well as, 11C-5-hydroxy-L-tryptophan positron emission tomography (PET) and 68Ga-DOTATOC-PET scan can be used for the investigation of metastatic rectal WD-NETs. Transabdominal U/S, CT, MRI and 18F-labeled deoxyglucose-PET scan should be considered for the metastatic PDECs.

Biochemical markers of Rectal NETs
CgA is not as useful biochemical marker compared to NETs in other organs. This can be explained by the small size of the rectal NETs in the majority of the cases. Another possible explanation may be that both L-cell type rectal NETs and PDECs usually express little or no CgA. Studies have shown that patients with non-metastatic tumours do not secrete in the circulation the hormones that are expressed in the neoplastic cells. Assessment of circulating PYY/PP and/or GLPs in metastatic L-cell type tumours may be of interest but limited experience exists. Tumours of the EC-cell type that have metastasized are rarely accompanied by the carcinoid syndrome; in these cases determination of U-5-HIAA can be of use. Other functioning tumors can be investigated and followed-up by specific hormone screening (e.g. ACTH-producing rectal NETs).

Treatment of Welldifferentiated Rectal NETs
Endoscopic resection of Welldifferentiated Rectal NETs
Before endoscopic treatment initiation the tumor invasion has to be evaluated with endoscopic ultrasound. Then, depending on the depth of invasion the following endoscopic procedures can be performed: Endoscopic mucosa resection (EMR), endoscopic submucosa resection-single ligation (ESMR-L), endoscopic submucosa resection-double ligation (ESMR-DL), endoscopic submucosa dissection (ESD), transanal endoscopic microsurgery (TEM). The overall rate of en bloc resection can reach 100%, usually with no or minor complications. After resection thorough histopathological assessment has to be performed, also with respect to radical excision.

Surgery of Welldifferentiated Rectal NETs
It has been suggested that rectal carcinoids measuring >2 cm in greatest dimension or demonstrating evidence of muscularis propria invasion should be treated as adenocarcinomas. Thus, an appropriate carcinoma-specific procedure should be performed.

Somatostatin analogues in Welldifferentiated Rectal NETs
Somatostatin analogues treatment can be initiated in the rare cases of functioning tumors, otherwise limited experience exists of the possible anti-neoplastic effect of these compounds in non-metastatic and metastatic cases.

Peptide Receptor Radiotherapy (PRRT) in Welldifferentiated Rectal NETs
PRRT (177Lu-DOTA0, Tyr3)-octreotate treatment of rectal WD-NETs with distant metastases seems to be promising.

A metastatic to the liver rectal WD-NET. Good response after PRRT.

A metastatic to the liver rectal WD-NET. Good response after PRRT.

Treatment of Poorly differentiated endocrine carcinomas
Chemotherapy in poorly differentiated endocrine carcinomas
Platinum-based treatment is initially indicated. If radical resection can be performed, it seems reasonable to continue with adjuvant chemotherapy during a period in an attempt to obtain a more durable effect.

Prognostic factors of Rectal NETs
Prognosis of welldifferentiated Rectal NETs
Rectal NETs appear to exhibit a low propensity to metastasize and, thus, are associated with a favourable prognosis, as reflected by the small percentage of metastatic tumors (4%) and a high 5-year survival rate (88.3%). Nevertheless, these excellent outcome data also may reflect the expeditious diagnosis of such tumors, usually based on endoscopic rectal evaluation after the early presenting symptoms of haematochezia, diarrhoeas or rectal pain. The tumor size and muscularis invasion are the two most important predictive criteria in the assessment of the malignant nature of these neoplasms. At the most recent Surveillance, Epidemiology, and End Results analysis the mean and median sizes of primary tumour were 1 cm and 0.6 cm, respectively (range 0.1 to 25 cm). Depth of invasion down to but not into the muscularis propria was identified in 93% of patients. Similarly, 4% of patients had invasion of the muscularis propria, and approx. 3% were found to have invasion beyond the muscularis propria. Overall, 4.1% of patients had regional lymph node metastasis, and 2.4% presented with distant metastasis at primary diagnosis. At least 60% of rectal NETs measure <1.0 cm in greatest dimension at primary diagnosis; these lesions metastasise in fewer than 2% of patients. In addition, metastatic spread in rectal NETs measuring between 1.0 cm and 1.9 cm and in lesions measuring >2 cm is evident in 10–15% and 60–80% of patients, respectively. Other factors correlated to the aggressiveness of the tumours are lymphovascular invasion, an increased mitotic rate (≥2/50 HPF) or Ki67 index ≥2%, central depression and ulceration of the mucosa covering the tumor.

Prognosis of poorly differentiated endocrine carcinomas
PDECs tend to give rise to local and distant metastases. Brain metastases are not uncommon.

5-year survival of Rectal NETs
I - welldifferentiated tumors
The 5-year survival of patients with rectal NET disease, who have distant metastases, is 15%-30%. For node positive rectal NET disease (without distant metastases at primary diagnosis), 5-year survival is 50%-70%. In contrast to this, rectal NETs without metastases and with a size smaller than 1 cm, as well as no signs of angioinvasion or infiltration of the muscularis propria are associated with an excellent 5 year survival of approx. 99%.

II - poorly differentiated endocrine carcinomas
The median survival of the patients suffering by these tumors is less than 12 months. The 5-year survival is less than 5% depicting the aggressiveness of these lesions.