Studies of hereditary endocrine tumors have been
especially fruitful, not only in defining the molecular
genetic basis of these complex diseases, but in
understanding the pathogenesis of the individual
component tumor of the syndromes as well as their
Most endocrine tumors involve a single endocrine gland, are
usually benign, and occur sporadically.
Rarely, endocrine tumors occur in a familial pattern where they
are multiple, involving more than one endocrine gland.
Over the past 50 years at least six multiple endocrine neoplasia
(MEN) syndromes have been described.
The genetic mutation causing each of these six MEN syndromes
has been identified, in many cases leading to improved diagnosis
and treatment of patients with a specific syndrome.
In 1954 Wermer described a family with
hyperparathyroidism and tumors of the pancreatic islet
cells and the pituitary gland.
2 to 3 per 100,000.
Males and females are equally affected.
All patients develop parathyroid hyperplasia by age 40.
50% develop malignant pancreatic islet cell tumors
(usually gastrinomas, less often insulinomas, and
rarely glucagonomas, or vasoactive intestinal
polypeptide secreting tumors [VIPomas]).
25% develop pituitary tumors (usually prolactinomas).
While familial hyperparathyroidism is most commonly a
component of MEN-1, it can occur in other settings, the
most notable being:
Familial (benign) hypocalciuric hypercalcemia (FHH)
The hyperparathyroidism jaw-tumor (HPT-JT)
Familial isolated hyperparathyroidism (FIHP).
An autosomal dominant disease characterized by
hypocalciuria, hypercalcemia, and parathyroid hyperplasia.
The calcium-sensing receptor (CASR), a critical regulator
of extracellular calcium homeostasis.
Expressed in cells of the parathyroid gland and the kidney
Sensitive to changes in the ambient calcium concentration
and when activated it inhibits parathyroid hormone (PTH)
secretion and the renal reabsorption of calcium.
With heterogenous inactivating mutations of the
CASR gene the parathyroid cell fails to sense properly
an increased serum calcium concentration, and the
resulting increase in PTH secretion causes FHH.
Conversely, activating mutations of the CASR gene
cause the parathyroid cells to sense that serum calcium
is “elevated” when it is actually normal and a resulting
decrease in the blood calcium level expressed as the
syndrome of autosomal dominant hypoparathyroidism
To date approximately 115 mutations (60% inactivating
and 40% activating) have been described in the CASR
HPT-JT is characterized by the autosomal dominant
occurrence of hyperparathyroidism, ossifying fibromas
of the mandible or maxilla, renal cysts or solid tumors,
and uterine fibromas.
Approximately 50 families with HPT-JT have been
reported and 80% of patients have
hyperparathyroidism, and in 15% of cases the
parathyroid tumors are malignant.
The syndrome of FIHP is a heterogenous condition.
Have germline mutations of MEN1, CASR, or HRP-JT.
Suggesting that the disease represents incompletely
expressed forms of MEN1, FHH, or HPT-JT.
Over 100 families with FIHP have been reported and in
most cases the causative genetic mutation is unknown,
although there are convincing data that it resides on
There is no relationship between genotype and
phenotype in patients with MEN-1, thus there is no
way to predict the presence or behavior of pancreatic
islet cell tumors or pituitary tumors.
There are important genetic mutations associated with
other hereditary and sporadic pituitary tumors.
Carney Complex (CNC)
Familial Isolated Pituitary Adenomas (FIPA)
Pituitary adenomas can occur as a component of CNC.
A familial disease characterized by:
2. Cardiac or cutaneous myxomas.
3. Spotty skin pigmentation.
4. Primary pigmented nodular adrenal disease.
5. Testicular tumors.
6. About 75% of patients exhibit subclinical increases in
growth hormone (GH), insulinlike growth factor-1 (IGF-
1), and prolactin.
7. Acromegaly occurs in about 10% of patients.
Pituitary adenomas can also occur as FIPA.
Of the 138 affected family members, 55 had prolactinomas,
47 had somatotropinomas, 28 had nonsecreting adenomas,
and 8 had adrenocorticotropic hormone–secreting tumors.
The incidences of a homogenous (single tumor) phenotype
and a heterogeneous tumors phenotype were
Affected patients were found to have no mutations in
either the MEN1 or PRKRA1A genes.
In 1968 Steiner et al. described a large family with
medullary thyroid carcinoma (MTC), pheochromocytomas,
hyperparathyroidism, and Cushing's syndrome.
All patients with MEN-2A develop MTC, approximately
half develop pheochromocytomas, and 30% develop
Less often MEN-2A is associated with cutaneous lichen
amyloidosis (CLA), which develops on the upper back and
serves as a precocious marker of the disorder, or
Hirschsprung's disease (HD), which is characterized by
loss of ganglion cells in variable segments of the large
Patients with MEN-2B develop MTC and
pheochromocytomas with the same frequency as
patients with MEN-2A, but rather than
hyperparathyroidism, they express a generalized
gastrointestinal neuromatosis and a characteristic
Patients with FMTC develop only MTC. Of patients
with hereditary MTC, 80% have MEN-2A, 15% have
FMTC, and 5% have MEN-2B.
Medullary thyroid carcinoma originates from C cells, which
are derived from the neural crest.
The C cells have great biosynthetic capability and secrete
the polypeptide hormone calcitonin (CTN) and the
glycoprotein carcinoembryonic antigen (CEA).
Plasma CTN serves as an excellent marker for MTC, and
presently its main use is in detecting persistent or residual
MTC following thyroidectomy.
The MTC is the most common cause of death in patients
with MEN-2A, MEN-2B, and FMTC, and the only effective
therapy is timely thyroidectomy as standard chemotherapy
and external beam radiotherapy are not useful.
The discovery that mutations in the RET protooncogene
cause MEN-2A, MEN-2B, and FMTC changed the
management of patients with both sporadic and hereditary
MTC and represents a paradigm for personalized genomic
DNA analysis for RET germline mutations is indicated in
patients with presumably sporadic MTC, as approximately
5% of them will be found to have hereditary disease.
It is imperative to screen the family members of patients
with newly found germline RET mutations, since they are at
risk for MTC and approximately half of them will be
Considering patients with familial cancer syndromes,
hereditary MTC fulfills each of the criteria necessary for
prophylactic removal of the organ at risk:
1. Near complete penetrance, such that virtually all patients
who have inherited a mutated allele will develop the
2. A highly reliable genetic test to detect family members
who have inherited a mutated allele.
3. The organ at risk is expendable or its function can be
4. Resection of the organ at risk can be performed with
5. There is a sensitive tumor marker, to determine whether
the malignancy has been prevented or cured following
The MEN Consortium Meeting in 2000 evaluated the
relationship between specific RET codon mutations
and the biological aggressiveness of hereditary MTC.
Based on combined clinical data the panel defined
three levels of thyroid cancer severity, on which to base
the timing of thyroidectomy
Patients with mutations in RET codons 609, 768, 790, 791,
804, or 891 (level 1) are at risk for developing MTC;
however, their tumors are generally more indolent and
develop at a later age than is the case in patients with other
RET codon mutations. Recommendation for thyroidectomy
in this group is controversial, and many clinicians base
their advice for thyroidectomy on plasma calcitonin levels.
In patients with mutations in RET codons 611, 618, 620, or
634 (level 2) thyroidectomy is recommended at or before 5
years of age.
Patients with MEN-2B and mutations in RET codons 883 or
918 (level 3) have the most severe form of MTC, and
thyroidectomy is recommended within the first 6 months of
Realizing the criticalness of removing the thyroid
gland while the MTC is curable, and understanding
that it is impractical to establish strict guidelines for
the timing of thyroidectomy based on the various RET
codon mutations, clinicians should err on the side of
advising thyroidectomy too early rather than too late.
This approach is strengthened by the fact that once the
MTC has spread beyond the thyroid gland it is virtually
incurable, as no chemotherapy or radiotherapy regimen
has proven effective.
Insulinomas, glucagonomas, gastrinomas, and nonfunctioning
endocrine tumors can all present as cystic lesions.
Isolated or associated with the multiple endocrine neoplasia
syndrome type 1 (MEN 1), which is characterized by the triad of
parathyroid, pituitary, and pancreatic lesions (3P’s).
Solitary, multiple, or diffuse; different histologic types may occur
in the same patient.
Gastrinomas, however, are an uncommon pancreatic neoplasm in
MEN 1 because most gastrinomas are located in the duodenum
rather than in the pancreas.
Insulinoma is the most common functioning islet cell tumor.
The clinical triad leading to the diagnosis is fasting hypoglycemia,
symptoms of hypoglycemia, and immediate relief of symptoms after
the administration of IV glucose.
Symptoms and signs are caused by both hypoglycemia and the
secondary release of catecholamines and include palpitations,
headache, confusion, pallor, sweating, slurred speech, and coma.
Despite this striking list of symptoms, the clinical presentation is often
Fasting hypoglycemia with no decrease in insulin level is confirmatory.
Approximately 10% of insulinomas are multiple, 10% are malignant,
and 10% of patients have hyperplasia rather than neoplasia.
Most insulinomas are small and hypervascular. Some contain
Malignant tumors tend to be large. Cystic lesions are rare.
Cystic insulinomas in 36-year-old woman with multiple endocrine neoplasia type 1. CT scan shows small cystic
masses (arrows) in body and tail of pancreas. Patient presented with primary hyperparathyroidism.
Gastrinoma is the second most common functioning islet cell tumor.
Most are sporadic and associated with the Zollinger-Ellison syndrome.
The initial manifestations are most often in young adults who have peptic
ulcer disease that suggests the diagnosis when ulcers are recurrent,
intractable, multiple, or in unusual locations.
Diarrhea due to the large volume of hydrochloric acid and a direct effect
of gastrin on the small bowel is common.
The diagnosis is confirmed by increased serum gastrin concentrations.
Gastinomas are frequently multiple, extrapancreatic, difficult to locate,
Hepatic metastases are associated with a poor prognosis, whereas patients
with metastases isolated to lymph nodes often have long-term survival.
The tumor size is variable, but pancreatic lesions average 3-4 cm. The
lesions are often hypervascular, so they may be visible on arterial phase CT
Rare cystic lesions have been reported.
Most lesions are malignant and present with equal incidence in
middle-aged men and women.
Most patients present with a necrolytic migratory rash and various
other elements of the “glucagonoma syndrome” including diabetes
mellitus, stomatitis, diarrhea, anemia, and weight loss.
The characteristic rash involves the lower extremities and the
perineum, begins with erythema and progresses to coalescent
blisters and pustules, and is pruritic.
An elevated plasma glucagon level establishes the diagnosis, but
there are often increased blood levels of other hormones, including
insulin, serotonin, and gastrin.
Approximately 50% of patients survive at least 5 years after
Tumor size is variable, but most are large and have metastasized
at the time of diagnosis.
Most are located in the distal pancreas and are vascular.
Tumors may be solid or contain central low-attenuation areas
on CT. Cystic lesions are rare.
Cystic glucagonoma in 34-year-old woman. CT scan shows large cystic mass in tail of pancreas. Patient had
diabetes and presented with characteristic eczematous dermatitis termed “necrolytic migratory erythema.”