Historically, carcinoids have long been known to be a morphologically distinct class of rare GI tumours that behave less aggressively than the more common adenocarcinoma. They arise from diffuse gastrointestinal endocrine system which is the largest single endocrine system of the body. The term ‘carcinoid’ however is today less well defined than ever before. It has resulted in terminological confusion.

The limitations of using ‘carcinoid’ as a collective term are:

1. It is extended to include all tumours with distinctive organoid morphology irrespective of their heterogeneous nature with respect to their biologic behavior i.e. the name refers to both benign and malignant tumours.

2. Morphologically identical tumours at different sites can show divergent prognosis.

3. The cell of origin can be different in all tumours. The tumours arising from these cells show differences in their respective locations, etiological factors, pathogenesis and also prognosis.

Hence use of the age old and well ingrained term ‘carcinoid’ is increasingly discouraged in favour of the term ‘Neuroendocrine tumour’.

The term neuroendocrine tumour by itself does not provide any specific information regarding the prognosis of these tumours. However, it certainly provides a scope for further categorization and qualification of a given tumour. This term is always to be used with the reference to the classification of neuroendocrine tumours in a specific location in the GI, thus providing the clinician with an accurate diagnosis to guide therapeutic strategies. The resultant system is logical both diagnostically and prognostically. This new proposed classification is discussed below.

Many different classification systems and types of nomenclature are used for GI- NETs. WHO has proposed a new classification based on the evidence provided by several studies examining various prognostic parameters viz. site, size, depth of invasion and functionality of the tumour. Over the years, the evidence in the published literature has shown that the following factors have prognostic significance in GI- NETs:

Size : Most of the evidence pertaining to significance of size is derived from retrospective studies. Tumours less than 1cm are benign while tumours more than 2cm usually are of higher grade.

Site : the prognosis of ileal and colonic carcinoids is worse than for either rectal or appendicecal tumours.

Depth of invasion : Non-functional NETs that are limited to mucosa or submucosa are usually low grade tumours. Tumours that infiltrate the muscularis and serosa often behave in a clinically malignant fashion.

Margins : The status surgical resection margins are important

Disease in surrounding mucosa : Disease that occurs in the surrounding mucosa like e.g. atrophic gastritis, inflammatory bowel disease and neuroendocrine hyperplasia should be included in the pathology report which essentially reflects the pathogenesis of gastric NET and in turn guides management.

Functioning tumours : Tumours with carcinoid syndrome usually herald a high stage disease with liver metastasis.

WHO has proposed a grading system of NETs. It is as follows:

(A) Well- Differentiated Neuroendocrine Tumour
Grade 1 ( Benign Behaviour) :
These are non functioning, cytologically bland tumours smaller than 1cm and confined to the mucosa/submucosa without angioinvasion

Grade 2 (Uncertain Malignant potential) :
Non- functioning, cytologically bland tumours, measuring 1 to 2 cm and are confined to the mucosa/submucosa. Angioinvasion may be noted (except in the jejunum/ ileum)

(B) Well-Differentiated Neuroendocrine Carcinoma :

Grade 3 (Low- grade malignancy) :
Non – functioning, cytologically bland tumours greater than 2cm, with or without angioinvasion and with extension beyond the submucosa. All functional well- differentiated tumours of any size are included in this category.
(C) Poorly Differentiated Neuroendocrine Carcinoma :

Grade 4 (High grade malignancy) :
Cytologically poorly differentiated tumours, functional or nonfunctional, of intermediate or small cell type.
The above grading system is incorporated in classification of NETs of each part of the GI tract. For example, gastric and small intestinal NETs are classified respectively as follows :

Stomach :

Benign : Non- functioning, cytologically bland tumours up to 1 cm in size limited to mucosa and submucosa without vascular invasion.

Uncertain malignant Potential : Non functioning, less than 2cm in size, limited to submucosa, with or without angioinvasion. Includes type 2 gastric NETs.

Low-grade Malignancy : Non functioning tumours > 2cm, extension beyond submucosa, includes all sporadic gastric NETs and all functioning tumours of any type and all antropyloric gastrinomas.

High-grade malignancy : Poorly differentiated functioning or non functioning tumours of intermediate or small cell type.

Stomach NETs, in addition are also classified into four types depending upon the etiology and pathogenesis :
Type 1 : Tumours arising on the background of chronic atrophic gastritis or as a manifestation of MEN type 1
Type 2 : Tumours in the setting of Zollinger-Ellison syndrome
Type 3 : Sporadic tumours
Type 4 : Sporadic poorly differentiated or mixed Neuroendocrine and epithelial tumours
The prognosis of each of these 4 types correlates closely with the classification given above. Type 1 and 2 tumours are almost always multiple but benign with only one series reporting lymph nodal metastasis in 8.5% cases. Anti H. pylori treatment or antrectomy to suppress hypergastrinemia can be performed. Type 3 tumours correspond with well differentiated Neuroendocrine carcinomas which are usually large and solitary. Although they are slow growing tumours as compared to conventional adenocarcinomas, the metastatic rate can be as high as 60% with liver mets in 50% of cases. Deaths are reported after a mean survival of 2 to 4 years. Surgery is the main treatment for primary as well as some metastatic disease. Type 4 tumours show uniformly poor prognosis with 75% patients dying within 1 year of diagnosis. Aggressive surgical approach along with chemotherapy is recommended.

Small Intestine :

Benign : Nonfunctioning, well differentiated tumour, </- 1cm, limited to mucosa and submucosa, no angioinvasion. Usually serotonin producing tumours in the terminal ileum.
Uncertain malignant potential : Same as benign except size upto 2cm.

Low Grade malignancy : Nonfunctioning well differentiated large tumour, > 2cm, or extending beyond submucosa or angioinvasion or both. Usually serotonin producing tumours of the terminal ileum, functioning tumour of any size and extension, serotonin producing tumour with carcinoid syndrome,sporadic gastrinoma of upper jejunum.

High grade Malignancy : Functioning or nonfunctioning poorly differentiated intermediate or small cell carcinoma.

NETs of small intestine differ from those of stomach where tumour size and association with other diseases are important. In addition to size, the NETs of small intestine are strongly associated with their functional features (especially those of duodenum).

In conclusion, the tumours of the diffuse neuroendocrine system of the GI for so long been called as ‘carcinoids’ have moved on to be designated as ‘neuroendocrine tumours’. A constellation of pathological parameters classifies morphologically similar tumours in prognostically distinct subsets. This classification gives comprehensive diagnostic and prognostic information useful towards management of neuroendocrine tumours of the GI tract. Thus it is emphasized that a pathologist should be aware of his or her role in the clinical management when it comes to ‘the carcinoids’ in light of new classification based on the published evidence.

References :
1. Fiona Grame-Cook : Surgical Pathology of the GI tract, pancreas, liver and Billiary system. P 483 - 505
2. Guido R., et al ECL cell tumour and poorly differentiated endocrine carcinoma of the stomach : Prognostic evaluation by pathological analysis. Gastroenterology 1999; 116: 532-542
3. Gunter K., et al : Pathology and Nomenclature of human gastrointestinal neuroendocrine ( carcinoid) tumours and related lesions. World J. of Surgery20, 132-141, 1996
4. Modlin IM., Sandor A: An analysis of 8305 cases of carcinoid tumours. Cancer 79: 813-829, 1997
5. Rosenburg JM., Carcinoid tumours of the colon. A study of 72 cases Am J. Surg 149: 775-779,1985
6. Werner Creutzfeldt : Carcinoid tumours : Development of Our Knowledge. World J. of Surgery 20, 126-131, 1996.