Carcinoid Tumors, GIST, and Lymphoma of GI

Question 1

Describe Type I gastric neuroendocrine tumors

Answer 1

Type I tumors represent 70% to 80% of all gastric endocrine tumors.

-associated with hypergastrinemia resulting from autoimmune (corpus-restricted) atrophic gastritis and, therefore, are found more commonly in elderly patients, particularly women, with atrophic gastritis and often are associated with pernicious anemia.

These tumors are small (<1 cm), confined to the oxyntic mucosa, and tend to be multiple and usually co-exist with multifocal ECL cell hyperplasia.

Gastric neuroendocrine tumors tend to be found incidentally, often in patients undergoing EGD as part of an evaluation for anemia.

Question 2

Describe Type II gastric neuroendocrine tumors

Answer 2

Type II gastric neuroendocrine tumors are associated with hypergastrinemia resulting from a gastrin-secreting tumor. They frequently are detected as part of the work-up for MEN-1 syndrome or for Zollinger–Ellison syndrome. In both instances the tumors are usually small (<1 cm) and show neither infiltrating nor pleomorphic features.

This type of neuroendocrine tumor is the most uncommon, representing only 5% to 8% of gastric neuroendocrine tumors.

Question 3

Describe Type III gastric neuroendocrine tumors

Answer 3

Type III (sporadic) neuroendocrine tumors are not associated with hypergastrinemia, are generally solitary, arise in otherwise healthy gastric mucosa, and are not accompanied by ECL cell hyperplasia.

These tumors, which represent approximately 20% of all gastric neuroendocrine tumors, usually are detected when they become symptomatic, either secondary to mucosal erosion and blood loss or metastasis. Because these events tend to occur only after the tumors reach a certain size, these tumors are usually larger than 1.5 cm, display infiltrating growth patterns with areas of necrosis, and show various degrees of pleomorphism.

Their proliferation index is high (mitotic count >20 per high-power field or a Ki-67 index > 20%). Type III neuroendocrine tumors have a generally poor prognosis with a mean survival of 28 months

Question 4

Where do carcinoid tumors arise from?

Answer 4

from neuroendocrine organs (e.g. the endocrine pancreas) and neuroendocrine-differentiated GI epithelia such as G cells in the antrum of the stomach

Question 5

Where are the majority of carcinoid tumors found?

Answer 5

the majority are found in the GI tract, with more than 40% being found in the small intestine. The tracheobronchial tree and lungs are the next most commonly invovled

Question 6

What pts typically get carcinoid tumors?

Answer 6

Peak incidence in 60s, but may appear at any age and symptoms are determined by the hormones produced.

Question 7

How might Type I gastric carcinoid tumors present?

Answer 7

-older pts. presenting with epigastric pain and anemia (If you see someone older than 40 with anemia and abdominal pain, you have to think CANCER. Weight loss and poor appetite increases likelihood)

-Endoscopy showing many (10+) small nodules in the **body and fundus** of the stomach

Question 8

How would a biopsy of a carcinoid tumor look?

Answer 8

aggregates of neuroendocrine cells consistent with hyperplasia or carcinoid tumors

Question 9

What is the most important prognostic factor for GI carcinoid tumors?

Answer 9

location

Question 10

Describe foregut carcinoid tumors

Answer 10

these are typically found in the stomach, duodenum proximal to the ligament of Treitz, and esophagus, and rarely MET (cured by resection) (This is particularly true for gastric carcinoid tumors that arise in association with atrophic gastritis)

Keep in mind that gastrinomas located in the pancreas and duodenum can arise (ZE syndrome) and are associated with PPI therapy

Question 11

Describe midgut carcinoid tumors

Answer 11

These often arise in the jejunum and ileum and are often multiple and tend to be aggressive. In these tmors, greater depth of local invasion, increased size, and presence of necrosis and mitoses are associated with poor outcome

Question 12

Describe hindgut carcinoid tumors

Answer 12

These arising in the appendix and colorectum are mostly found incidentally. Those in the appendix (the most common tumor of the appendix!) are benign, while rectal carcinoids are more likely to produce hormones and manifest with abdominal pain and weight loss and MET

Question 13

What is autoimmune gastritis?

Answer 13

Accounts for 10% of chronic gastritis cases and is marked by antibodies to and loss of parietal cells (and intrinsic factor) resulting in:

• reduced serum pepsinogen I levels (loss of chief cells)
• antral endocrine cell hyperplasia
• vitamin B12 deficiency
• achlorhydria (acid production decreased but gastrin increased due to lack of feedback, causing antral G cell hyperplasia)

Question 14

Where does autoimmune gastritis occur?

Answer 14

There is diffuse damage of the oxyntic (Acid-producing) mucosa within the body and fundus, with damage to the antrum and cardia typically absent

Question 15

What are some sequelae of autoimmune gastritis?

Answer 15

Atrophy, pernicious anemia, adenocarcinoma, carcinoid tumor

Question 16

What are some associations of autoimmune gastritis?

Answer 16

other autoimmune disease; thyroiditis, DM, graves disease

Question 17

Describe what is occurring in this biopsy of autoimmune gastritis

Answer 17

Autoimmune gastritis is marked by diffuse atrophy of the oxyntic mucosa of the body and funding, causing it to appear markedly thinned, with loss of rugal folds. Neutrophils may be present, but the main inflammatory infiltrate is composed of lymphocytes, macrophages, and plasma cells

Intestinal metaplasia and Neuroendocrine hyperplasia may also be seen (usually use an immunostain to find)

Question 18

How would Type I gastric carcinoid tumors be treated most often?

Answer 18

Usually you try to remove the source of gastrin, the antrum, in an antrectomy, and pts. recover

Question 19

What are your thoughts?

Answer 19

Definitely thinking cancer, and the symptoms are consistent with carcinoid syndrome releasing serotonin/histamine etc.

Question 20

What additional tests should be ordered for pt 2?

Answer 20

Options:

CT scan (CT shows HYPERdense lesions indicating METS from NE tumor; adenocarcinoma METs are HYPOdense)

Urine 5-HIAA and Chromogranin levels

EUS

Octreotide scan

Biopsy of liver lesion

Question 21

Answer 21

Nuclei may have salt;pepper pattern

Carcinoid EVREYWHERE looks the same (cant tell where its coming from in histology)

Question 22

What other immunostains would be positive in this tumor?

Answer 22

Chromogranin, synaptophysin, and CD56

Question 23

What is carcinoid syndrome?

Answer 23

The production of vasoactive substances/serotonin from carcinoid tumors that produce episodes of cutaneous flushing, sweating, bronchospasm, colicky abdominal pain, and diarrhea

Question 24

Carcinoid syndrome VERY HIGHLY suggests METs. Why?

Answer 24

Because tumors confined to the intestine release their vasoactive substances to be subjected to first-pass like effects in the liver

•Occurs in 10% of patients with carcinoid tumors, typically ileal tumors with liver metastases - bioactive products can be released directly into systemic circulation. Also can be overcome with large tumor burden and hormones secreted into nonportal circulation.

Question 25

What urine assay is fairly diagnostic for carcinoid syndrome?

Answer 25

High urine 5-hydroxyindole acetic acid (5-HIAA)

Question 26

What is Zollinger-Ellison Syndrome?

Answer 26

Gastrinoma of pancreatic, duodenual, or peripancreatic soft tissue origin that cause severe peptic ulceration (along with gastric acid hypersecretion, weight loss and diarrhea) that are:

• typically multiple
• identical to those found in the general population but unresponsive to therapy
• may be found in the jejunum

Question 27

How is ZE Syndrome diagnosed?

Answer 27

• Fasting gastrin level >1000 pg/ml with gastric pH below 5
• Secretin stimulation test

Gastrin levels 0, 2, 5, 10, 15 & 20 min after IV Secretin

Increase in gastrin of >200 pg/ml (In these pts secretin will paradoxically INCREASE gastrin levels)

(sensitivity 83%, specificity 100%)

Question 28

Why do pts with ZE Syndrome have diarrhea?

Answer 28

They have diarrhea because pancreatic enzymes are activated at pH 5+ so hypergastrin levels will not allow them to be activated

Question 29

How should ZE Syndrome be managed?

Answer 29

Surgical resection is indicated for solitary, non-metastatic disease

All pts should receive high-dose PPIs, and long acting somatostatin analogs have shown to be effective

Question 30

What are the tx options for metastatic ZE Syndrome?

Answer 30

oStreptozocin/doxorubicin or temozolomide

oResection, Trans-arterial chemo-embolization(TACE), Radiofrequency ablation (RFA), Orthotopic liver transplantation (OLT)

Question 31

What is Menetrier disease?

Answer 31

hypoproteinemic hypertrophic gastropathy; A rare, acquired, premalignant disease of the stomach characterized by massive gastric folds, excessive mucous production with resultant protein loss, and little or no acid production. The disorder is associated with excessive secretion of transforming growth factor alpha (TGF-α)

Question 32

Characteristics of Menetrier disease

Answer 32

-irregular enlargement of the gastric rugae in the body and fundus with the antrum typically being spared (cause unknown)

Question 33

What is this showing?

Answer 33

hypertrophic gastropathy- doubling of oxyntic mucosal thickness due a 5x increase in the no of parietal cells in ZE Syndrome

Question 34

Bump is hard located in the distal body of the stomach. Submucosal covering suggests a GIST

Question 35

What is the most common mesenchymal tumor of the abdomen?

Answer 35

GIST (more than half of these occur in the stomach)

Question 36

How do GISTs present?

Answer 36

Symptoms are usually related to mass effects or mucosal ulceration with the clinical presentation ranging from asymptomatic to very aggressive (gastric GISTs are typically less asggressive than intesitnal ones)

• Behaves depending on size and histology
• More common manifestations: incidentally found, GI bleeding, abdominal mass, abdominal pain

Question 37

Notice how this pts symptoms are vastly different from pt. 3 but they both have GIST

Answer 37

Question 38

How do GISTs appear grossly?

Answer 38

Gastric GISTs are usually solitary, well circumscribed, fleshy, SUBMUCOSAL masses with signs of hemorrhage (METs may form multiple small serosal nodules or fewer larger ones in the liver- spread outside the abdomen is uncommon)

Question 39

How do GISTs appear histologically?

Answer 39

composed of elongated spindle cells or plumper epitheliod cells

Question 40

Approx 75-80% of GIST tumors have oncogenic, gain of function mutations of the gene encoding what?

Answer 40

tyrosine kinase c-KIT (GISTs appear to arise from, or share a common stem cell with the interstitial cells of Cajal, which express c-KIT, and are located in the muscularis propria where they serve as pacemaker cells for gut peristalsis)

check for expression of CD117

Question 41

What are the major morphologic patterns of GIST?

Answer 41

Question 42

T or F. GISTs can be benign or malignant

Answer 42

T. Hard to tell which GIST are benign and which are malignant (2 mitoses phpf suggests malignancy)

Question 43

What is the Carney Triad?

Answer 43

a nonhereditary syndrome of unknown etiology seen primarily in young females that includes:

• gastric GIST,
• paraganglioma, and
• pulmonary chondroma.

Question 44

There is also an increased incidence of GIST in individuals with ______

Answer 44

neurofibromatosis type 1

Question 45

What is the tx for metastatic GIST?

Answer 45

Can give a tyrosine kinase inhibitor Imatinib Mesylate

Question 46

Question 47

Lymphomas more likely to have fever, sweats, and weight loss

Secondary involvement is common (10% in limited and 60% in advanced NHL)

Question 48

In USA gastric is the most common; the majority are extra-nodal marginal zone B lymphoma of the mucosa associated lymphoid tissue (MALT) type or diffuse large B-cell lymphoma.

Primary small intestinal lymphoma is uncommon in western countries but is 75 % of the Middle East and mediterranean Basin (Why ??)

Burkitt lymphoma is 50 times more frequent in Africa

Question 49

MALT

Answer 49

Question 50

•65 yo history of hepatitis C

Screening CT: “Gastric tumor with diffuse perigastric adenopathy and extragastric extension”tumor

Answer 50

• 73 year old Caucasian male consulting in August 2011 for failure to thrive and abdominal pain
• CT scan of the abdomen: “ wall thickening, multiple periaortic lymph-nodes, multiple liver masses and splenomegaly”

Gastric ulcer consistent with DLBCL.

“ Judging from the profound prolonged cytopenias (HCT: 26, Plt: 56, WBC:3.9); he had BM involvement ”

TTx: R-CHOP

Patient died 3 months after diagnosis

Question 51