Tumours of the small intestine D37.2

Langhans was the first to describe a malignant neuroendocrine tumor of the small intestine as a polypoid tumor as early as 1867. One year later, in 1888, Lubarsch reported on two patients who had multiple tumors in the ileum.

The carcinoid syndrome was first described by Ransom in 1890 (Scott 2018).

The term "carcinoid" was introduced by Oberndorfer in 1907 and the term "carcinoid syndrome" was introduced by Thompson in 1954 (Ghadimi 2022).

The WHO published the first classification system in 1980, in which the majority of neuroendocrine tumors were referred to as "carcinoid tumors" (Scott 2018).

The most recent WHO update was in 2017 with the introduction of the category "NET G3" (Ghadimi 2022)

Small bowel tumors are benign or malignant tumors in the area of the small bowel.

A distinction is made between benign and malignant tumors:

• Benign tumors include e.g:
  • Adenomas: These occur in approximately 25% of all benign tumors of the small intestine. They may appear as single polypoid lesions or as papillary villous adenomas (Kasper 2015).
  • Angiomas: Angiomas take the form of hemangiomas or telangiectasias. They are very rare (Zeuß 2016),but often cause bleeding (Kasper 2015).
  • Small bowel endometriosis
  • Fibromas
  • Leiomyomas: These tumors arise from intestinal smooth muscle cells and are predominantly intramural (Kasper 2015).
  • Lipomas: They have a radiolucent appearance and are usually located intramurally (Kasper 2015). They are predominantly found in the distal small intestine (Zeuß 2016).
  • Neurinomas (Herold 2022), including e.g. neurofibroma, ganglioneuroma, schwannoma (Hirner 2008).
  • Intestinal nodular hyperplasia: Often an incidental finding. Frequently found in the terminal ileum. Affected are predominantly patients with chronic variable immunodeficiency. Degeneration has not been described so far.
  • Brunner hamartomas and heterotopias: These occur preferentially in the proximal duodenum and very rarely lead to clinical symptoms. Malignant transformations have been described in isolated cases (Zeuß 2016).

• Malignant tumors include, for example:
  • Adenocarcinomas: They are among the most common primary malignancies of the small intestine, accounting for approximately 50%.
  • gastrointestinal stromal tumors = GIST
  • Malignant lymphomas: These neoplasms account for about 20% of all malignancies of the small intestine and are classified as non- Hodgkin's lymphomas (Herold 2022). At diagnosis, about 70% of tumors are already in stage IV (Siewert 2006).
  • Neuroendocrine tumors = NET (occur in about 29 % [Brücher 2001]) such as:
    • Carcinoids
    • Ganglioneuromas
    • Somatostatinomas
    • VIPomas (Zeuß 2016)
  • Sarcomas (Herold 2022)
  • Ampullary carcinomas: These often arise from biliary or pancreatic ducts.
  • Leiomyosarcomas: They are not infrequently palpable through the abdominal wall, being > 5 cm in diameter.
  • Immunoproliferative small intestinal disease (IPSID): This is a B- cell tumor (Kasper 2015).

Another classification distinguishes between primary and secondary tumors:

• Primary tumors:
  • These are all tumors that have their cells of origin in the small intestine and occur between the pylorus and cecum (Zeuß 2016)
• Secondary tumors:
  • Metastasis e.g. of a melanoma (Kasper 2015).
  • Infiltration of neighboring organs (Ludwig 2010) such as by bronchial carcinoma, melanoma, breast carcinoma, thyroid car cinoma (Zeuß 2016).

The 2017 WHO- classification divides neuroendocrine neoplasms (NET) into:

• Highly differentiated NEN
  • NET (neuroendocrine tumor) grade 1: The Ki67- index is < 3 %, the mitotic rate < 2 / 10 HPF.
  • NET grade 2: Ki67 index is 3-20%, mitotic rate is 2-20/10 HPF.
  • NET grade 3: Ki67 index > 20 %, mitotic rate > 20 / 10 HPF
• Low-differentiated NEN (neuroendocrine neoplasms)
• NEC (neuroendocrine carcinoma) grade 3: Ki67- index is > 20 %, mitotic rate > 20 / 10 HPF (Ghadimi 2022).

Small bowel tumors are very rare, accounting for < 5% of all gastrointestinal tumors (Herold 2022). The ratio of benign to malignant tumors is 1: 3 in the small intestine (Schöffski 2006).

• Malignant small bowel tumors:

Malignant tumors of the small intestine account for approximately 1 - 3% of all malignant tumors of the gastrointestinal tract. The incidence of malignant tumors of the small intestine is increased in countries with high fat diets such as Finland, UK, Canada, USA and decreased in Nigeria, Japan, India. A low predominance is shown in the male gender (Brücher 2010).

Neuroendocrine tumors (NET) have increased significantly in frequency since the 1970s (Ghadimi 2022) (Howe 2017).

A particular form of small bowel lymphoma, also known as immunoproliferative small bowel disease (IPSID) or Mediterranean lymphoma or alpha heavy chain disease, diffusely affects the entire small bowel and was first described in Oriental Jews and Arabs (Kasper 2015).

Frequency of individual tumors:

• benign tumors such as:
  • Adenoma (30%)
  • Leiomyoma (25%)
  • Lipomas (15 %)
  • Neurinomas (10 %)
  • angioma (10 %)
  • fibroma (5 %)
  • Endometriosis (rarity)

(Hirner 2008)

• malignant tumors such as:
  • adenocarcinoma (47 % - 63 % [Zeuß 2016])
  • intestinal carcinoid (28 %)
  • malignant GIST (13 %)
  • malignant lymphoma (12 %) (Simon 2005)
  • neuroendocrine tumors = NET (25 - 44 % [Zeuß 2016]).
  • immunoproliferative small bowel disease (IPSID [Kasper 2015])

Immunology plays a major role in the development of malignant small bowel tumors (Brücher 2010), as do genetic factors (Schöffski 2006).

Malignant lymphomas in the small intestine are frequently found in patients with Z. n. organ transplantation, autoimmune diseases or congenital immunodeficiency syndromes (Kasper 2015).

- Carcinoid tumors arise from argentaffin cells of Lieberkühn's crypts in an area that embryologically belongs to the midgut. They have low malignant potential, but invasion and metastasis can occur, leading to carcinoid syndrome (Kasper 2015)

- Hereditary, autosomal-dominant, nonpolyposis colon cancer with tumors in the small intestine and other organs (Kasper 2015).

Risk diseases for malignant tumor of the small intestine are:

- M. Crohn's

- Peutz-Jeghers syndrome

- neurofibromatosis

- Gardner syndrome

- Familial polyposis coli (Brücher 2010)

- non-tropical sprue

- cystic fibrosis

- M. Recklinghausen

- Muir Torre syndrome

- M. Caroli (Schöffski 2006)

Protective factors for small bowel malignant tumor are:

- fast chyme transit time (reduces contact with potential carcinogens)

- fluid consistency of the small intestinal chyme (reduces the intensity of exposure of potential carcinogens)

- predominantly alkaline environment

- highest activity of benzpyrene hydroxylase (this converts carcinogenic benzpyrene into metabolites that are less toxic)

- high IgA concentration (neutralizes viruses and/or carcinogens)

- high regeneration rate of the small intestinal mucosa

- relative sterility of the small intestine compared to the colon (probably causes a reduced release of carcinogenic substances)

(Brücher 2010)

Benign tumors of the small intestine occur preferentially in the 5th and 6th decade of life (Kasper 2015).

The age peak of malignant tumors of the small intestine is usually between 60 - 70 years (Brücher 2010).

Benign tumors of the small intestine:

- 27 % in the duodenum

- 33 % in the jejunum

- 40 % in the ileum (Schalhorn 2004)

Malignant small bowel tumors:

- 32 % in the duodenum

- 34 % in the jejunum

- 34% in the ileum (Brücher 2001)

Because abdominal symptoms are often vague, it is not uncommon to delay diagnosis of this rare tumor. Suspected small bowel tumors are:

- recurrent, unexplained episodes of crampy abdominal pain

- intermittent bowel obstruction without evidence of inflammatory bowel disease or previous abdominal surgery

- intestinal obstruction in adults

- Chronic intestinal bleeding with negative endoscopic and conventional examination (Kasper 2015).

Symptoms of a small bowel tumor may include:

- abdominal pain

- recurrent subileus (Herold 2022)

- intestinal bleeding (Kasper 2015).

Additional symptoms of malignant tumors:

- fever

- weight loss

- loss of appetite (Kasper 2015)

Symptoms of immunoproliferative small intestinal disease (IPSID) include:

- chronic diarrhea

- steatorrhea

- vomiting

- abdominal pain

- drumstick finger (Kasper 2015).

Timely diagnosis is often difficult in this regard because, on the one hand, malignant tumors of the small intestine are rare (Brücher 2010), symptoms are sometimes nonspecific, and the sensitivity of conventional radiologic imaging to detect this type of cancer is limited (Puccini 2018).

Malignant tumors of the small bowel can not infrequently be palpated through the abdominal wall, especially leiomyosarcomas (Kasper 2015).

Conventional X-ray examination of the upper and lower digestive tract.

This type of radiographic examination usually shows unremarkable findings, which is why the diagnosis of a small bowel tumor is often delayed (Kasper 2015).

Sonography

Sonography plays a rather minor role in the diagnosis of small bowel tumors (Scott 2018). Bowel wall thickening, larger tumors, evidence of subileus, free enteric fluid can be well visualized on sonography (Zeuß 2016), as can liver metastases (Scott 2018).

Intestinal barium examination

This examination can detect a small bowel tumor. Diagnostic accuracy here is higher when barium is administered via a nasogastric tube inserted into the duodenum (Kasper 2015).

Abdominal CT.

Multiphasic computed tomography is the most common diagnostic imaging modality for small bowel tumors (Scott 2018).

MRI- examination according to Sellink / Hydro- MRI.

In Sellink MRI, an osmotically active solution is delivered via a jejunal probe. The sensitivity is 95% and for the terminal ileum 60%, the specificity is 83%.

In hydro-MRI, the osmotically active solution is administered orally. The sensitivity is 97% and 63% for the terminal ileum, and the specificity is 97% (Berthold 2012).

For the detection of liver metastases, MRI- examination is more sensitive than CT (Scott 2018).

Enteroscopy as single and double enteroscopy.

In many patients, this examination can visualize the entire small bowel (Scott 2018).

Video capsule endoscopy.

In this procedure, a miniature camera is swallowed (Herold 2022). In this way, it is usually possible to view the entire small intestine (Scott 2018).

Possibly angiography (Herold 2022).

Laboratory chemistry may demonstrate anemia, as well as a chronic inflammatory syndrome (Scott 2018).

• Tumor markers are:
  • In NET:
    • Chromogranin A (major tumor marker).
    • 5- hydroxyindoleacetic acid
    • Neuron-specific enolase (NSE) (Rinke 2018).
  • In adenocarcinoma:
    • CEA = carcinoembryonic antigen (Scott 2018).

In NET, the following hormone markers are found:

• Gastrin
• Serotonin
• Somatostatin (Rinke 2018).

There are more than 35 known histological variants of small intestinal tumors.

They are histologically divided into:

- epithelial tumors

- non-epithelial tumors

- malignant lymphomas

- hamartomatous polyps

- hyperplastic polyps

- secondary tumors such as metastases (Simon 2005).

For NEN- specimens, both HE and PAS staining should be performed to differentiate well vs. poorly differentiated (Rinke 2018).

Clinical and radiological examinations are difficult to predict the histology of small bowel tumors (Kasper 2015).

- Adenocarcinoma:

Radiologically not reliably distinguishable from chronic ulcer disease or Crohn's disease (Kasper 2015).

- ileus

- enteral hemorrhage

- Carcinoid syndrome (Herold 2022)

Benign tumors:

In this case, surgical resection is recommended for some tumors (see "Surgical Therapy").

Malignant tumors:

Treatment consists of surgical removal of the tumor (see "Surgical Therapy"). Chemotherapy is possible if histology is appropriate (Herold 2022).

In some malignant tumors of the small intestine, radiatio is performed after complete resection of the tumor (Kasper 2015).

Chemotherapy is usually short-term systemic treatment over 3 cycles with combined chemotherapy (Kasper 2015).

• Gastrointestinal stromal tumors:

For gastrointestinal stromal tumors (GIST), treatment with imatinib is recommended (Herold 2022). These are tyrosine kinase inhibitors (Gnant 2008).

It can be used:

- Neoadjuvant:

This is done preoperatively for tumor reduction (Gnant 2008). Response is to be assessed after 4 - 12 months, after which surgery is performed.

Recommended dosage Imatinib: 400 - 800 mg / d (Hübner 2018).

- Adjuvant:

Adjuvant, the administration of imatinib is recommended for intermediate and high risk over a multi-year period.

Recommended dosage imatinib: 400 mg / d (Hübner 2018).

• Malignant GIST:

In GIST, metastasis is already present in approximately 50% of patients at diagnosis.

If there is not yet metastasis, adjuvant chemotherapy with imatinib for at least 3 years is recommended as standard in addition to surgery (see "Surgical Therapy").

Dosage recommendation imatinib: 800 mg / d (Zeuß 2016).

• Malignant lymphomas:

Because intestinal lymphoma is a very rare tumor type, few studies exist. Patients should therefore be linked to an appropriate study center as early as possible. The therapy itself depends on the subtype and is based on the treatment of nodal non- Hodgkin lymphomas (Zeuß 2016).

• Neuroendocrine tumors (NET or NEN = neuroendocrine neoplasms [Rinke 2018]):

Provided it is a localized stage, preoperative treatment with octreotide or lanreotide as a depot preparation should be given.

Dosage recommendation Octreotide: 2 x 100 - 150 µg s. c. / d.

Dosage recommendation Lanreotide: increasing dose of 60 - 120 mg deep s. c. every 4 - 6 weeks (Zeuß 2016).

In already metastatic stage, treatment with octreotide has been shown to be beneficial. Dosage recommendation: 2 x 100 - 150 µg s. c. / d (Zeuß 2016).

Symptomatic measures include:

- Avoidance of alcohol and sports in case of flush

- Loperamide in case of diarrhea

- Inhaled beta- 2- sympathomimetics in bronchial asthma.

It is recommended to present patients with NET in centers specialized for this purpose (Zeuß 2016).

• Immunoproliferative small bowel disease (IPSID):

In early stages of IPSID, oral antibiosis with e.g. tetracycline often leads to an improvement of symptoms. In later stages, chemotherapy is administered (Kasper 2015).

Benign tumors of the small intestine:

- Adenomas:

These should be surgically removed because villous adenomas have a high rate of degeneration (Zeuß 2016).

- Hemangiomas:

In these rarely occurring tumors, surgical removal is only necessary in exceptional cases such as severe bleeding (Zeuß 2016).

- Leiomyomas:

Leiomyomas should be removed even if the histology is benign, as there is an increased complication rate with larger tumors (Zeuß 2016).

- Intestinal nodular hyperplasia:

Surgical resection is not necessary because, on the one hand, degeneration has not been described so far, and on the other hand, recurrent hepatocytic hyperplasia occurs after resection (von Schweinitz 2013).

- Lipomas:

Surgical resection is indicated in symptomatic cases such as stenosis or hemorrhage (Zeuß 2016).

- Brunner hamartomas and heterotopias:

In appropriate symptomatology such as bleeding, stenosis, endoscopic or open surgical resection is performed (Daum 2008).

Malignant tumors of the small intestine:

The only potentially curative treatment is complete surgical resection of the tumor, including locoregional lymph nodes (Puccini 2018).

Because extensive intra-abdominal disease often already exists at the time of diagnosis for malignant tumors, complete resection is usually not possible (Kasper 2015) and is not recommended (Puccini 2018).

- Malignant GIST:

Primary surgery with R0 resection should be performed in patients who do not yet show metastasis. Adjuvant chemotherapy with imatinib should be standard (see "Internal Therapy").

(Zeuß 2016)

- Neuroendocrine tumors (NET):

If the tumor is in a localized stage, RO resection should be the gold standard after appropriate preoperative therapy with octreotide (see "Internal Therapy") (Zeuß 2016).

The prognosis of benign tumors of the small intestine is generally good, that of malignant tumors poor (Herold 2022). In Germany, the mortality rate is constant at 320 per year (Brücher 2001).

In patients with a localized malignant tumor, the probability of sustained remission or cure is about 75%, and in patients with inoperable lymphoma, about 25% (Kasper 2015).

Chemotherapy can lead to intestinal perforation (Kasper 2015).

Adenocarcinoma:

For the most common malignant tumor of the small intestine, adenocarcinoma, the 5-year survival rate depends on the stage (see "Tumor staging"):

- Stage I: 65 %

- Stage II: 48

- Stage III: 35

- Stage IV: 4 % (Zeuß 2016)

Neuroendocrine tumors (NET):

The 5-year survival rate for NETs, regardless of stage, is approximately 60% (Zeuß 2016).

Immunoproliferative small bowel disease (IPSID):

The course of IPSID is characterized by exacerbations and remissions. Patients often ultimately die from malnutrition and emaciation. However, aggressive lymphoma may also develop (Kasper 2015).

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