Carcinoid Tumors

Oberndorfer introduced the term carcinoid in 1907 to describe tumors that behaved more indolently than adenocarcinomas. These are composed of monotonous sheets of small round cells with uniform nuclei and cytoplasm. They are neuroendocrine tumors and share certain common features with other NETs:

1. Monotonous cellular morphology
2. No reliable discriminator of malignancy - invasion and mets are the two features - so FNAC is useless.
3. Have electron dense secretory granules in EM scopy
4. Have small clear vesicles corresponding to the synaptic vesicles of neurons
5. Synthesize and secrete several BIOACTIVE amines and peptides eg:
1. NSE - General marker for APUDomas
   
2. Serotonin - Specific marker for Carcinoids - MC foregut and hindgut carcinoids - these are Masson Reaction -ve
   
3. Chrmogranin - General marker for NET
   
4. Synaptophysin - General marker for NET
6. React with Silver  - two reactions known:
1. Fixation of Silver and reduction - ARGENTAFFIN reaction (Masson) - Midgut carcinoids have this postive and serotonin negative
   
2. Fixation of Silver only - ARGYROPHILLIC reaction
   

Other examples of Neurendocrine tumors are:

• Pheochromocytomas
• MTC
• Pancreatic Endocrine Tumors
• Malignant Melanomas

As per the latest figures of the SEER database:

1. Foregut carcinoids account for 38.9 % of all carcinoids
2. Midgut carcinoids account for 46.8 % of all carcinoids
3. Hindgut carcinoids account for 18.5 % of all carcinoids

The most common sites for carcinoids are as follows:

1. Trachea/ Bronchi and Lungs = 25%
2. Small Intestine (Duodenum + Ileum + Jejunum) = 19%
3. Rectum = 18%
4. Colon and Appendix = 10%
   
5. Stomach = 6%

Features of Carcinoids according to site of origin:

• Midgut carcinoids are different from the rest two as:
• These often secrete serotonin and result most commonly in Carcinoid Syndrome
• Bone Mets are uncommon
• Blood and Urine biochemistry will revel the secretory pattern - 5 -HT and 5-HIAA
• The tumors reduce silver - argentoffin reaction positive.
  
• The the secretory granules are pleomorphic in shape but have a uniform density
• Uniform grwoth pattern
  
• Foregut and hindgut carcinoids on the other hand share some features like:
• Secrete 5-HTP not serotonin
• Therefore carcinoid syndrome is less common - however atypical carcinoid syndrome is common
• Bone Mets are common
  
• Blood and urine biochemistry reveal 5-HTP and 5-HIAA as well Histamine secretion
• Fix but NOT REDUCE silver - agyrophilic but not argentoffinic
• Secretory granules are uniform in shape but have variable density.
• Mixed Growth pattern - Trabecular or Solid
• Although these tumors are less commonly associated with carcinoid syndrome per se however they are more commonly associated with carcinoid crisis.
  

More differences can be found in this spreadsheet.
Foregut includes:

• UGI tract upto the Duodenum 2nd part
• Respiratory Tract
• GB / Pancreas/ Bile duct
  

Midgut includes:

• GI tract upto the transverse colon right half - drainage of SMA
  
• Ovary /Testis
• Cervix
• Liver

Special Features of Carcinoids at different sites - Important as classification systems rely on the site wise division

• Small Intestine:
• Overall account for almost 20% of all carcinoids
• Most occur within 2 feet  of the ileocecal valve (70%)
  
• Most are < 2 cm size (70%)
  
• Are associated with serotonin production and carcinoid syndrome
• Are associated with a fibrous desmoplastic reaction - so present with obstruction or ischemic necrosis
• Mets are seen in 70% if the size is > 2cm
• MC site of mets is the liver (60%)
• Median age of onset is 63 yrs.
• MC symptoms are related to abdominal pain and symptoms related to GI bleeding.
• Detection is difficult:
• Somatostatin Receptor Scintigraphy and CT are better detecting hepatic mets and bone mets - SRS should be the initial study for localization of mets. The approved agent for the scan is Indium Diethylenetriamine pentaacetic acid phenylanalys octreotide.
  
• Angiography more sensitive than CT for detecting liver mets.
• Treatment:
• For any small intestinal carcinoid the recommendation is wide local resection with dissection of the lymphnode areas with primary anastomosis.
  

• Stomach:
• Three subtypes are known:
• Type I: Associated with atrophic gastritis leading to secondary hypergastrinemia associated with MEN - I
  
• Type II: Associated with ZES in the setting of MEN - I and associated with primary hypergastrinemia
• Type III: Sporadic in nature and not associated with hypergastrinemia
• Paradoxically the Type III is least common and most aggressive. These are more commonly associated with carcinoid syndrome.
• MC detected by UGIE like duodenal carcinoids.
• Treatment:
• Endoscopic excision if tumor is < 2cm and for Type I and II carcinoids
• For tumors > 2 cm and Type III - Total gastrectomym with nodal clearance is recommended.
  
• Rectal:
• These are the most common type of hindgut carcinoid - the colonic carcinoids are MC seen in the region of the ileocecal valve
• Account for almost 18% of all carcinoids.
  
• These are commonly occuring in the anterolateral wall in the upper 1/3rd of the the rectum
• The tumors are mostly less than 2 cm size (c.f. small intestine carcinoids)
• Mets are seen in 70% if the size > 2cm
• Median age of onset is usually older around 66 yrs
• MC symptoms are bleeding and alteration of bowel habits.
• Detected by endoscopy.
• Treatment is:
• Localized the size is < 2cm.
• APR is recommended for tumors > 2 cm or those with muscalaris propria invasion - however all patients will die of metastatic disease
• For appendicular carcinoids < 1cm simple appendictomy is adequate
• For appendicular carcinoids > 1 cm a Rt hemicolectomy is recommended.
  
• Pulmonary Carcinoids:
• These accout for 25% of all carcinoids
  
• Not related with smoking.
  
• Considered to be a part of a continuum which includes the entity of small cell carcinoma
• 3 / 4 subtypes are said to occur: The classification scheme dividing these into 4 types given by Hage et al is the latest scheme
  
• Typical carcinoids are type I (KCC -I) - <2 mitoses per 2 mm2 - No necrosis - 85 - 100% 5 yr survival
  
• Atypical Carcinoids are Type II (KCC - II) - > 2 but <10 mitoses per 2 mm2 - punctate necrosis - 40 -70% 5 yr survival
  
• Large cell neuroendocrine tumor (KCC - III) - > 10 mitosis per 2 mm 2 and large areas of necrosis - 15 - 40% survival
  
• Small cell cancer
• Median age of onset is 63 years.
• MC symptoms are pneumonia, hemoptysis, and cough.
• MC detected on radiological investigations - on CXR these appear as opacities with sharp margins - Hilar nodal mets are usually absent.

The Important Prognostic Features associated with carcinoid tumors are:

• Site of presentation: Small bowel and pancreatic carcinoids have the poorest prognosis while appendicular and pulmonary are the best.
• Size of the tumor : Size > 2 cm associated with mets
• Pathological features:
• Atypical carcinoid in lung - necrosis and more mitosis
• Type III carcinoid in stomach - not associated with hypergastrinemia
• Extent of tumor invasion
  
• Presence of nodal invasion
• Mets - particularly hepatic mets.
• Highest probablity of metstatic disease is seen in pancreatic and small bowel carcinoids
• Lowest probablity is seen in rectal and laryngeal mets.
  
• Yound age
• Presence of carcinoid syndrome and high urinary 5 -HIAA excretion are associated with poorer prognosis.
  

The overll 5 yr survival for patients with localized disease is around 80% , for regional diseas is 50 -60% and those with mets 20%.