Multiple Endocrine Neoplasia

(MEN)

Bhoj Raj Neupane

GMC

Source: [Link]/[Link]/[Link]
Multiple endocrine neoplasia (MEN)
Autosomal dominant, inherited endocrine tumor syndromes characterized by-
• a different pattern of benign & malignant tumors
• in different endocrine glands.
• several types: Type 2 is more predictable than others.
1. MEN 1- (Wermer syndrome): Mutation in the ‘MEN1’ gene located on chr. 11q13
Approx. 90%- inherited, & 10%- random mutation.
2. MEN 2A- (Sipple syndrome): Mutation in the RET oncogene on chr 10q11.
3. MEN 2B- Mutation in the RET oncogene, located at chromosome 10q11.
4. MEN 4- Mutation to CDKN1B gene
Rare type
Similar symptoms to MEN 1 but different genetic cause
 MEN

Multiple endocrine neoplasia type 1

MEN type 1 (Wermer’s syndrome)
• Prevalence: 4 - 20 cases / 100,000 pop /yr.;
n
♂=♀
• Penetrance: high, almost 100% of mutation carriers develop the syndrome.
Characterized by tumors of-
• Parathyroid glands (pHPT) - 90-100 %
• Pancreatic islet cells (gastrinoma, insulinoma & glucagonoma) - 50- 80 %
• Pituitary gland (prolactinoma / non-functioning) - 30-60 %
May develop - Lipomas (5-10%),
- NET of thymus, bronchi, & stomach (3-10% )
- Tumors of the thyroid, adrenal cortex (40-50%), & CNS.
 MEN

Multiple endocrine neoplasia type 1

MEN-1- tends to present as primary hyperparathyroidism, &
- less commonly as ZES, insulinoma, or a pituitary tumor.
Screening:
• Plasma Ca++,
• Gastrin,
• Glucose,
• Insulin,
• VIP, PP,
• Prolactin, GH, β-HCG yrly
 MEN

Multiple endocrine neoplasia type 1

Hyperparathyroidism: frequently the 1 detectable abnormality of MEN-1.
st

generally has 4-glands enlargement.

Surgery: 3.5-gland parathyroidectomy, or
Total parathyroidectomy with autotransplantation of 0.5. & cervical thymectomy
• Cures in > 90% of cases.
• Graft-dependent recurrent HPT- up to 50% of cases.
⇒ Resecting a portion of the auto-grafted gland.
Screening: of asymptomatic kindred member- yearly S. Ca recommended.
 MEN

Multiple endocrine neoplasia type 1

Pancreatic islet cell tumors: account for most of the morbidity / mortality.
• Diffusely involved, with islet cell hyperplasia, multiple & multifocal tumors.
• One hormone syndrome dominant.
• Gastrinomas (most common), but can be any type.

• Treatment goal- Relief of symptoms & Cure / palliation of the malignant process.
• Surgery to control hormonal excess & prevent liver metastasis
• Gastrinomas located in duodenum or pancreatic head- PPPD
• Before surgery, R/O other gland tumors.
 MEN

Multiple endocrine neoplasia type 1

Pituitary tumors:
• Prolactinomas (most common), but can be-
• GH, ACTH–producing, & non-functioning tumors.

Treatment:
Medical: Treatment of choice. Bromocriptine
• Inhibits prolactin production &
• Reduce tumor bulk & obviate the need for surgical intervention.
Surgery: Trans-sphenoidal hypophysectomy (if medical treatment fails).
 MEN

Multiple endocrine neoplasia type 1

Adrenal tumors & other organ manifestations:
• Mostly non-functioning adenomas;
• Rarely, adrenocortical carcinomas or pheochromocytomas.
• Very rarely: NET of lung, thymus, stomach, duodenum & small bowel.

Treatment: Functional adrenal tumors need operation

Non-functional adrenal tumors, if > 4 cm- resected
 MEN

Multiple Endocrine Neoplasia type 2

Sipple syndrome: Characterized by tumors of-
• Medullay Thyroid Cancer (100%): plays the key role,
• Pheochromcytoma (40-50%),
• Parathyroid hyperplasia > adenoma (25-35%),
• Genetic testing should be performed on all suspected individuals.
• Genetic counseling for parents is crucial prior to prophylactic surgery.
• Prophylactic thyroidectomy is indicated for all RET-mutation carriers:
- in the 1st yr of life for MEN-2B.
- before age 5 years in MEN-2A.
• In > 50% of patients with MTC, the cancer recurs after primary surgery.
 MEN

Multiple endocrine neoplasia type 2

• GI manifestations- abdominal pain, distention, constipation, Hirschsprung.
• MTC generally occurs earlier than pheochromocytoma or HPT.
• Exclusion of pheochromocytoma is must in all patients prior to thyroidectomy.

• MTC combined with pheochromocytoma alone is called Sipple’s syndrome.

 MEN

Multiple endocrine neoplasia type 2B (3)

Comprises of - MTC,
• Pheochromocytoma
• Marfanoid habitus
• Hypergnathism of the midface,
• Oral mucosal neuromas &
• Intestinal ganglioneuromatosis

• MTC is particularly aggressive in these patients.

• MEN-2B pts also have multiple GI symptoms & megacolon.
 MEN

FMTC
• Characterized only by the hereditary development of MTC without other
endocrinopathy
• MTC is generally more indolent in these patients.

Prophylactic thyroidectomy recommendation:

• Within the first 6 m of life for individual with MEN2B
• By 5-10 yrs of age for individual with MEN2A & FMTC
However these depends of the patient’s personal & family history.
Neuro Endocrine Tumors (NET)
Bhoj Raj Neupane
GMC
 NET

Neuroendocrine tumors (NET)

Neuroendocrine cells have traits similar to that of
• Nerve cells &
• Hormone-producing cells.

Neuroendocrine tumors are rare.

Can occur anywhere in the body (single or clustered cell) but

mostly occur in the lungs, appendix, small intestine, rectum, and pancreas.

• Slowly growing / fast growing.

• Functional / Non-functional.
 NET

Neuroendocrine tumors (NET)

Cells of the system secrete- / produce-
Neuroendocrine markers- synaptophysin, chromogranin A, & neurone-specific enolase
Peptide hormones stored in granules- serotonin, somatostatin, PP, or gastrin.
Chromogranin A is utilized as a tumor marker.
Functional test for NET of gut: Serotonin metabolite 5-HIAA in urine

Diagnosis & treatment depend on-

• Type of tumor,
• Location,
• Excess hormone production +/-,
• Aggressiveness and
• Metastasis (±).
 NET

Neuroendocrine tumors (NET)

Pathology:
• Neuroendocrine cells ⇒ hyperplasia / tumors (Carcinoids).
• Different growth patterns: benign to high-grade undifferentiated cancer.
• NET - with histological pattern (benign, low- / high-grade malignant) &
- anatomical site (e.g. stomach, ileum) (WHO, 2000).
• Relative distribution of NET in different organs is ➨
• Risk factors:
• MEN-1, MEN-2
• Von Hippel-Lindau disease
• Tuberous sclerosis
• Neurofibromatosis
 NET

Neuroendocrine tumors (NET)

Features: don’t always cause S/S at first,
depends on type of tumor, its location & excess hormones
Due to tumor-
• Pain from the growing tumor
• Lump felt Due to excess hormones-
• Feeling unusually tired • Skin flushing
• Losing weight without trying • Diarrhea
• Frequent urination
• Increased thirst
• Dizziness
• Shakiness
• Skin rash
Neuroendocrine tumors (NET)
Grade is determined by both the mitotic count (2 mm2) & Ki-67 (a protein in cells),
which are both markers of how fast the tumor cells grow and divide.

Grade Mitotic Count Ki-67

The WHO grades for NETs:
Grade 1 Less than 2 Less than 3% • Grade 1 (low-grade): cells divide at a low rate & therefore grow slowly.
• Grade 2 (intermediate-grade): cells divide at an intermediate rate.
Grade 2 2 to 20 3% to 20%
• Grade 3 (high-grade): cells divide at a fast rate & therefore grow quickly.
Grade 3 More than 20 More than 20%

Degree of differentiation.
• Well differentiated: cells look more like healthy cells.
• Poorly differentiated: cells look less like healthy cells.
Poorly differentiated NECs are divided into large-cell & small-cell type.
 NET

Neuroendocrine tumors (NET)

Treatment: Depends on the type of tumor, location, excess hormone production.
Treatment options:
• Surgery:
• Chemotherapy:
• Immunotherapy
• Radiation therapy
• Targeted drug therapy:
• Medications to control excess hormones
• Peptide receptor radionuclide therapy: Lutetium
• Active surveillance (monitoring without a treatment)
• Liver-directed treatment
• Somatostatin analogs Source: Neuroendocrine tumors: Types of Treatment [Link] Editorial Board, 202
 NET

NET of the bronchi

Etiology:
• About 1–2% of all lung tumors are NET.
• Etiology: unknown except with MEN-1 syndrome.

Clinical features:
• Central tumors: Coughing, dyspnea & / or fever if obstruction / pneumonia.
• Peripheral tumors: No symptoms for a long time.
 NET

NET of the bronchi

Diagnosis:
• Radiography, CT scan,
• Somatostatin receptor scintigraphy (SRS),
• Bronchoscopy & biopsy.

Treatment: Surgical resection (treatment of choice).

• Benign / low-grade malignancy- Parenchyma sparing resection; no LN dissection.
• Undifferentiated NET - Wide resection (as in ordinary lung cancer).
• Metastatic disease - Somatostatin analogues or
Chemotherapy (Cisplatin, Etoposide/streptozotocin & doxorubicin)
 NET

NET of the stomach

• Rare; ̴5% of all NET of GIT. Incidence: 2 cases/million pop n/yr.
• Types of gastric NET:
Treatment
Type Histological pattern Site & location Causative factors
choice
Benign, Non-functional, < 1 cm, Gastric body, ECLomas in atrophic gastritis,
1 well differentiated Mucosa / submucosa hypergastrinemia
Endoscopic
resection
Benign, or 1-2 cm, angio-invasive, ECLomas with hypergastrinemia
2 Low-grade malignant Mucosa / submucosa due to gastrinoma in MEN-1

Low-grade malignant, > 2 cm, invasive, Sporadic, ECLomas

3 differentiated Beyond submucosa not related to hypergastrinemia Surgical
resection
Intermed. / small cell type
4 High-grade malignant
Different sizes Causative factor not known Prognosis poor
 NET

NET of the stomach

Types 1 & 2 arise from the entero-chromaffin-like (ECL) cells in gastric mucosa.
Grow in linear / nodular pattern.
Type 1 & 2 tumors (ECLomas):
Most of stomach NET (80%);
Occur mostly in elderly women
• Do not cause symptoms & usually detected during EGD.
• Hyper-gastrinemia may cause symptoms of PUD.
Treatment: Endoscopic resection.
Antrectomy: Recurrent dis., multiple (>6) tumor, size >1 cm & submucosal infiltration.
 NET

NET of the stomach

Type 3 tumors- malignant, sporadic & solitary.
• Presentation: upper GI bleeding.
• Size usually > 2 cm & often have LN & liver metastases.
• Serum gastrin is normal.
Treatment: Gastrectomy & LN dissection & resection of liver metastasis.

Type 4 tumors- Present as large ulcerating malignancies similar to adenoca &

Should be treated accordingly.

Prognosis of types 3 & 4 ⇒ poor.

 NET

NET of small bowel

Most of GI NET are found in small bowel.

Produce serotonin & may cause ‘carcinoid’ syndrome.
Pathology: Duodenum-rare site.
• Arise from enterochromaffin (EC) cells,
• Secrete serotonin & substance P.
• Solitary / multiple, almost always malignant.
Multiple NETs in small bowel causing large LN mets in
the mesentery

• Metastasize early to regional LNs & liver.

 NET

Neuroendocrine tumors (NET)

Symptoms: caused by either primary tumor or lymph node mets.
• Abdominal pain: Acute / chronic, recurrent / persistent,
• Ileus, lumen obstruction, lower GI bleeding (rarely).
Symptoms may be due to liver metastases.
• → Carcinoid syndrome.
Cardiac symptoms (60%)
• of PS & TS, enlargement & thickening of Rt. Atrium
 NET

Neuroendocrine tumors (NET)

Diagnosis:
• Imaging: USG, CT scan & MRI will not show primary because of small size but
will show mesenteric lymph node & liver metastases.
• 5-HIAA in a 24-hour urine +ve in larger tumors only if mets present.
• Octreotide (SRS) scan: best method for staging of NET
(provided they are large enough & have high somatostatin receptor density)
Treatment:
Resection of the bowel primary tumor(s) & mesenteric LN metastases.
Liver metastases treated by chemotherapy or embolization,
even liver transplantation
• Somatostatin & its analogues: symptomatic treatment of ‘carcinoid’ syndrome.
 NET

Carcinoid tumor: (Argentaffinoma)

• Carcinoid tumors arise in argentaffin tissue (Kulchitsky cells of the crypts of Lieberkühn)
• Carcinoid tumors make: Serotonin, PG, 5-HTP, Subs. P, kallikrein, histamine, dopamine, & neurotensin.
• Metabolized in the liver;
• With liver metastasis they are released into systemic circulation & cause symptoms.
• 20 - 30% may have functional syndrome.
Features
• Most common site: Vermiform appendix.
• Frequently found in the distal third.
• Carcinoid tumor: 1 in 300–400 appendices subjected to HPE
• 10 times more common than other appendix tumor.
• Symptoms of subacute or recurrent appendicitis.
 NET

Carcinoid tumor: (Argentaffinoma)

Features
1. Flushing- most common
2. Diarrhea- secretory, > 10 motions, > 1L /day volume; persists despite fasting
3. Bronchospasm → asthma, wheezing
4. CCF
5. Abd. cramping
6. Peripheral edema
7. Heart: palpitations: 50% of pts
8. Fibrosis, arthropathy, increased skin pigmentation
 NET

Carcinoid tumor: (Argentaffinoma)

Pathology: Grossly feels moderately hard &
On sectioning: yellow tumor between the intact mucosa & peritoneum.
M/E:- small tumor cells, arranged in small nests within the muscle
- a characteristic pattern using immunohistochemical stain for chromogranin B.
Carcinoid tumor of the appendix rarely metastasize.
Treatment:
• Appendicectomy usually sufficient.
• Right hemicolectomy: if cecal wall involved,
tumor > 2 cm size,
[Link]
LNs involved.
 NET

Carcinoid crisis
Preoperative stress associated endocrine emergency
Manifested by: Circulatory collapse triggered by an acute release of vasoactive amines
into circulation triggered by any type of stress.
Features: Profound flushing, Bronchospasm, Tachycardia, widely & rapidly fluctuating BP
Investigation: Echocardiography
ChromograninA measurement gold-standard test for Dx of NET, carcinoid tumors
Treatment:
Somatostatin analogs: Octeotride, Lanreotide improve symptoms in 88% of patients
Alpha interferon useful
Telotristat, a tryptophan hydroxyl inhibitor reduce symptoms
Prognosis: median survival < 1 to 3 years