SPECIAL ARTICLE
Familial Multiple Endocrine Neoplasia
The First 100 Years
J. Aidan Carney, MD, PhD, FRCPI, FRCP
Abstract: In 1903, Erdheim described the case of an acromegalic
patient with a pituitary adenoma and three enlarged parathyroid
glands. Fifty years later, Underdahl et al reported 8 patients with
a syndrome of pituitary, parathyroid, and pancreatic islet adenomas.
In 1954, Wermer found that the syndrome was transmitted as
a dominant trait. In 1959, Hazard et al described medullary (solid)
thyroid carcinoma (MTC), a tumor that later was found to be
a component of two endocrine syndromes. The first of these
described by Sipple in 1961 comprised pheochromocytoma, MTC,
and parathyroid adenoma. The second, described by Williams et al in
1966, was the combination of mucosal neuromas, pheochromocy-
toma, and MTC. In 1968, Steiner et al introduced the term ‘‘multiple
endocrine neoplasia’’ (MEN) to describe disorders featuring
combinations of endocrine tumors; they designated the Wermer
syndrome as MEN 1 and the Sipple syndrome as MEN 2. In 1974,
Sizemore et al concluded that the MEN 2 category included two
groups of patients with MTC and pheochromocytoma: one with
parathyroid disease and a normal appearance (MEN 2A) and the other
without parathyroid disease but with mucosal neuromas and
mesodermal abnormalities (MEN 2B). Later, additional nonendo-
crine conditions (von Recklinghausen neurofibromatosis and von
Hippel-Lindau disease) were found accompanying other more
recently described familial MEN syndromes, indicating that these
diseases are very complicated disorders.
Key Words: endocrine tumors, multiple endocrine neoplasia,
dominant inheritance, familial syndrome, medical history
(Am J Surg Pathol 2005;29:254–274)
D uring the past century, the multiple endocrine neoplasia
(MEN) syndromes have emerged as an important group
of diseases. The clinical and pathologic features of several
such syndromes have been described, laboratory tests for them
have been devised, causative genes have been identified, and
diagnosis of the syndromes in asymptomatic patients can
today be accomplished by molecular genetic techniques.
Combinations of endocrine tumors may occur sporad-
ically by chance or also as the manifestation of genetically
From the Department of Laboratory Medicine and Pathology (Emeritus
Member), Mayo Clinic, Rochester, MN.
Reprints: J. Aidan Carney, MD, PhD, Department of Laboratory Medicine and
Pathology, Mayo Clinic, 200 SW First Street, Rochester, MN 55905
(e-mail:carney.aidan@mayo.edu).
Copyright Ó 2005 by Lippincott Williams & Wilkins
254
mediated syndromes. Best known of the sporadic combina-
tions is the association of parathyroid adenoma and papillary
carcinoma of the thyroid,27 which, in most cases,62 is probably
the result of the unrelated development of two relatively
common tumors in the same patient. The sporadic nonfamilial
endocrine tumor associations have attracted little attention and
are not discussed further here.
Elucidation of the classic familial MEN disorders was
greatly facilitated by progressive improvements in methods for
histologic identification of endocrine cells and their tumors, by
advances in the clinical laboratory in measuring concen-
trations of hormones, and by innovations in radiologic imaging
of tumors. In the1960s, electron microscopy showed that
peptide and catecholamine-producing cells and their tumors
contained membrane-bound organelles called secretory gran-
ules. In some instances, the variable size, shape, and density of
the granule cores permitted tentative identification of the
hormone content. But as recently as the 1970s, two silver
impregnation methods, the Masson argentaffin and Grimelius
argyrophil techniques, were the only histologic methods
available for identification of endocrine cells and their tumors.
In the late 1970s, application of immunocytochemical
methods, using monoclonal antibodies to peptide hormones
and other hormones, revolutionized the identification of
endocrine cells and their tumors. More recently, in situ
hybridization histochemistry has permitted recognition of
endocrine cells in which the protein hormone content was not
otherwise detectable.
In the clinical laboratory, measurement of hormone
concentrations in urine has progressed from colorimetric and
chromatographic methods to bioassay, radioimmunoassay,
chemiluminescence, and liquid chromatography tandem mass
spectrometry. A series of previously unknown hormones,
including calcitonin, somatostatin, and glucagon, was discov-
ered. Methods of tumor detection by radiologic methods
benefited from the introduction of computed tomography, ra-
dioisotope scanning, ultrasonography, scintigraphy, magnetic
resonance imaging, and positron emission tomography.
Most recently, molecular genetic techniques have been applied
to the investigation and diagnosis of the familial MEN
syndromes.
As with any burgeoning field, it is not surprising that
the initial nomenclature for the MEN syndromes was unsatis-
factory (Table 1). The same syndrome was given different
titles by different authors. Sometimes syndromes were distingui-
shed by Roman numerals and sometimes by Arabic numerals,
sometimes using lower case letters, elsewhere employing
capital letters. The terms ‘‘multiple endocrine adenomatosis’’
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Am J Surg Pathol  Volume 29, Number 2, February 2005
TABLE 1. Titles Proposed for the MEN Syndromes
Pituitary, Parathyroid, MTC;
Pancreatic Islet Pheochromocytoma;
Reference Cell Adenomas Parathyroid Adenomas
Steiner et al70 MEN, type 1 MEN, type 2
Sizemore et al68
Chong et al17 MEN type 2A
Khairi et al45
Gagel et al32 MEN 2A
MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma.
and ‘‘multiple endocrine neoplasia’’ were used interchange-
ably. Individual authors were not always consistent in their use
of nomenclature. This resulted in a confusing terminology. In
order not to perpetuate this, I use the currently accepted
nomenclature for the established syndromes in this article
rather than the original nomenclature, unless there is reason to
use the original.
In this account of the emergence of the MEN syndromes
and certain intimately related conditions, such as medullary
thyroid carcinoma (MTC), I include descriptions of certain
Mayo Clinic patients who were seen during the years leading
up to and overlapping with description of the classic MEN
syndromes (from 1945 through 1975) to illustrate several
points. First, they show that although unusual cases may be
recognized and carefully documented, they may not be
reported in the literature. Thus, when the original report of
a rare entity finally appears, it may be just the tip of an iceberg.
Second, the cases illustrate the difficulties experienced by
clinicians and pathologists as they struggled to categorize
patients who had undescribed disorders or incompletely
evolved disorders or both. These experiences emphasize the
importance of searching institutional files and the literature
determinedly when unusual cases are encountered and, in this
connection, they show some of the realized opportunities and
missed opportunities of the times. As becomes evident later in
this article, these early Mayo Clinic experiences were not
unique.
The MEN story began in 1903 when Jacob Erdheim29
was probably the first to describe a patient with tumors of two
endocrine organs, the pituitary gland and the parathyroid
glands. Exactly 50 years later, in a publication ushering in the
MEN era, Underdahl et al74 reported the cases of 8 patients
with tumors of three endocrine organs, the pituitary gland, the
parathyroid glands, and the pancreatic islets of Langerhans. In
1962, Sipple66 reported the association of carcinoma of the
thyroid gland and pheochromocytoma. Six years later, Steiner
et al70 introduced the term ‘‘multiple endocrine neoplasia’’ to
describe three combinations of endocrine tumors. These were
familial pituitary, parathyroid, and pancreatic islet cell tumors
(‘‘multiple endocrine neoplasia), type 1’’ [‘‘MEN type 1’’]),
familial pheochromocytoma, MTC, and hyperparathyroidism
(‘‘multiple endocrine neoplasia, type 2’’ [‘‘MEN 2’’]), and
nonfamilial parathyroid tumors and papillary thyroid carci-
noma (‘‘multiple endocrine neoplasia, type 3’’[‘‘MEN 3’’]).
In 1973, Sizemore et al68 concluded that the MEN 2
category described by Steiner et al included two distinct
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Familial Multiple Endocrine Neoplasia
Papillary Mucosal Neuromas;
Thyroid Carcinoma; Mesodermal Dysplasia;
Parathyroid Adenoma MTC; Pheochromocytoma
MEN, type 3
MEN, type 2b
MEN, type 2B
MEN, type 3
MEN 2B
groups of patients with MTC and pheochromocytoma: 1)
patients with hyperparathyroidism and a normal physical
appearance and 2) patients without parathyroid disease but
with an abnormal physiognomy due to labial and eyelid
mucosal neuromas and mesodermal abnormalities. Sizemore
et al suggested the title ‘‘multiple endocrine neoplasia, type
2b’’ for the group without parathyroid disease (Table 1) and
‘‘neuroma phenotype’’ for the constellation of mucosal
neuromas and mesodermal abnormalities (dolichocephaly,
marfanoid habitus, paucity of subcutaneous fat, poor skeletal
muscle development and muscle weakness, prognathism,
dental abnormalities, pes cavus or pes planus, slipped femoral
capital epiphysis, scoliosis, and lordosis). In 1975, Chong
et al17 suggested that the combination of MTC, pheochromo-
cytoma, and parathyroid disease in patients with a normal
appearance be referred to as MEN type 2A.
PITUITARY ADENOMA, ENLARGED
PARATHYROID GLANDS, AND PANCREATIC
ISLET CELL TUMORS
In 1903, when this story begins, Erdheim29 (Fig. 1), in
a wide-ranging article, included description of the autopsy
findings in the case of a 42-year-old acromegalic man. The
pituitary gland was markedly enlarged by a tumor that had
pushed remnants of the original gland to the periphery. The
parathyroids were grossly red and abnormally soft. Three were
large, measuring 12 3 5 3 3 mm, 17 3 6 3 3 mm, and 11 3 6
3 4 mm. The fat content of the glands was conspicuously low.
Between 1912 and 1952, at least 13 cases were reported
that had various combinations of adenomas or hyperplasia of
the pituitary, parathyroids, and pancreatic islets. In 1927,
Cushing and Davidoff18 encountered small adenomas of two
parathyroid glands (the other two glands were not identified),
a pancreatic adenoma, and adenomas of both adrenal glands at
autopsy in an acromegalic patient, in addition to the expected
pituitary adenoma. The pancreatic lesion was almost certainly
an islet cell tumor (Fig. 2). Regarding the extratumoral islets of
Langerhans, the authors stated that: ‘‘were it not for their
unusually large size and possible increase in number (they)
would pass as normal in all respects.’’ The patient also had
a lipoma of the thigh.
A similar case was described by Lloyd50 who in 1929
reported findings in the case of a 22-year-old woman with an
inoperable, nonfunctioning pituitary adenoma. At autopsy, two
parathyroid glands contained multiple adenomas and the
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Carney
FIGURE 1. Jacob Erdheim (1874–1937), pathologist and
director of the Institute of Morbid Anatomy, City Hospital,
Vienna.
FIGURE 2. The circumscribed tumor featured a trabecular-
alveolar pattern supported by a delicate stroma and abuts on
normal pancreas. Reproduced by permission from Cushing and
Davidoff (Figure 64).18
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Am J Surg Pathol  Volume 29, Number 2, February 2005
pancreas showed nine islet cell adenomas. Lloyd commented,
‘‘The pancreatic tissue contains many normal islands of
Langerhans, a goodly number of which are unusually large.’’
He interpreted the findings thus: ‘‘It seems more than likely
that they [the anatomic changes in the three endocrine tissues]
are related, but the evidence is insufficient to draw such
a conclusion definitively.’’
Neuroma Phenotype and Nonpapillary
Thyroid Carcinoma (MEN 2B)
A 17-year-old adolescent girl attended Mayo Clinic in
1947 because of disfiguring enlargement of her lips and
eyelids, which had been present since birth (Fig. 3A). She said
that she would be the happiest person in the world if she could
get rid of the mouth and eyelid growths because of their
unsightliness. No one else in her family looked like her. She
complained also of an occasionally painful neck mass. Later,
she had a daughter, who was born in 1956 (Fig. 3B) (see the
‘‘September 1973’’ section).
The patient was thin, 165 cm tall, and weighed 40 kg.
She had a ‘‘peculiar body configuration,’’ muscle weakness,
and pes cavus, Her facial appearance was striking: the face was
long (dolichocephaly) and the nasal root broad; the lips were
thickened and rubbery with multiple yellow masses; and the
eyelids appeared to be everted and had nodules. The tongue
was studded with pink, pea-sized nodules, and the buccal
mucosa and palate had similar lesions. The corneal nerves
were thickened. There was an egg-sized tender mass in the
right lobe of the thyroid. Plastic reconstructive surgical
procedures were performed on the patient’s lips and eyelids.
The excised tissues were variously interpreted as a ‘‘neurino-
ma,’’ ‘‘neurofibromatosis,’’ and ‘‘neurofibroma(s).’’ The clin-
ical diagnosis was neurofibromatosis. Cervical exploration re-
vealed tumors in both lobes of the thyroid; the right-sided
tumor had virtually replaced the lobe, penetrated the thyroid
capsule, and metastasized to cervical lymph nodes. Subtotal
thyroidectomy was performed. The tumors were interpreted as
‘‘grade 1 nonpapillary carcinoma.’’ Pathologic reevaluation
later showed that they were MTCs (Fig. 3C, D), a tumor that
had not been described in 1947. The patient did not return to
Mayo Clinic. At age 23 years, she had spells of dizziness,
palpitation, and hypertension. A clinically palpable left adrenal
pheochromocytoma was resected. At age 26 years, during
labor, headache and paroxysmal hypertension developed.
The hypertensive spells persisted after delivery, and a right
adrenal pheochromocytoma was resected at age 28. She
died in 1964 at age 35 years of ‘‘acute adrenal insufficiency.’’
The following diagnoses were made during her last hospitali-
zation: 1) Addison’s disease, 2) carcinoma of the thyroid with
lung metastases, 3) hypoparathyroidism, 4) neurofibromatosis,
5) postoperative pheochromocytoma, and 6) Marfan syndrome.
In hindsight, the patient had the classic features of
the MEN 2B syndrome. The pathologic features of the labial
and eyelid mucosal lesions in the syndrome were detailed in
1958 by Bazex and Dupré,5 who, like Wagenmann,80 and
Froboese,31 interpreted them as true neuromas because
microscopically they were composed of coiled and twisted
enlarged nerves.
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FIGURE 3. Facies and metastatic MTC

in MEN 2B. A, Seventeen-year-old
adolescent girl with a long face,
massively thickened lips, and appar-
ent eversion of the eyelids. B, Twelve-
year-old daughter of patient in A has
features very similar to her mother’s.
C, Cervical lymph node metastasis of
thyroid carcinoma, showing a largely
structureless growth pattern of mod-
erate-sized cells with acidophilic cy-
toplasm and eccentric nuclei (barely
perceptible). Focally, the cells are
palisaded. D, Immunoperoxidase
staining (performed in 2003) was
positive for calcitonin.

Bilateral Pheochromocytoma in 3 Siblings blood pressure from 190/140 mm Hg to 118/88 mm Hg in 2

Roth et al64 reported the cases of 3 siblings who attended
Mayo Clinic in 1951, each with bilateral pheochromocytomas.
Their father had ‘‘Bright’s disease’’ and hypertension; he died
of a stroke at age 42 years. There was no other information
about him.
The first sibling, an 18-year-old woman, complained of
blurred vision. Systolic/diastolic blood pressure was 260/160
mm Hg. She had experienced episodes of palpitation followed
by weakness for 5 years. A phentolamine test lowered the
minutes. Pheochromocytoma was suspected. Abdominal
exploratory surgery revealed bilateral multilobulated pheo-
chromocytomas; these were resected, leaving a portion of each
adrenal gland.
The patient’s 28-year-old sister visited her in the hospi-
tal. On inquiry, the visiting sister’s history was even more
suggestive of pheochromocytoma than the patient’s. A phentol-
amine test was positive for pheochromocytoma. Bilateral
lobulated adrenal tumors were found at surgery and excised.

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Carney Am J Surg Pathol  Volume 29, Number 2, February 2005

Inquiry was made concerning their 25-year-old brother,

who was apparently well. So far as the sisters knew, he did not
have hypertension and apparently was in good health, for he
had just served 3 years in the Army. When he came to visit his
sisters, he was advised to undergo examination for pheochro-
mocytoma. The history disclosed that he had had episodes of
mild hand tremor and pallor. Such episodes were particularly
likely to occur when he played poker, and the tremor
frequently indicated to his companions that he held good
cards. They nicknamed him ‘‘Shakey.’’ Pharmacologic tests
were positive for pheochromocytoma. Abdominal exploration
revealed bilateral multilobulated pheochromocytomas. The
tumors were resected, leaving a portion of each adrenal gland.
(For follow-up of the family, see the ‘‘September 1961’’
section).
Neuroma Phenotype and Bilateral Solid
Nonpapillary Carcinoma of the
Thyroid (MEN 2B)
A 14-year-old girl admitted to Mayo Clinic in 1952
complained of recent enlargement of a neck mass that had
been present since she was 5 years old. The patient was tall and
extremely thin; she weighed 36 kg. The blood pressure was
110/60 mm Hg. Photographs show probable enlargement of
her lower lip, and the late A. B. Hayles, MD, who examined the
patient, told me that in retrospect she had oral mucosal
neuromas. There were visible masses in both lobes of the
thyroid gland. The patient was operated on for probable
bilateral papillary carcinoma. Pathologically, bilateral solid
nonpapillary carcinoma of the thyroid with cervical lymph
node metastasis was found. Review later showed that the
tumors were MTC. (For follow-up, see the ‘‘November 1959’’
section).

ASSOCIATION OF PARATHYROID, PITUITARY,

AND PANCREATIC ISLET CELL ADENOMAS
(MEN 1)
In an article published in 1953, Underdahl and his Mayo
Clinic colleagues74 (Fig. 4) provided exquisite clinical and
pathologic detail concerning 8 complicated cases featuring
tumors of the pituitary gland, the parathyroid glands, and the
pancreatic islets. The findings were supplemented by those in
14 reported cases with at least two of the three tumors.
Underdahl et al stated: ‘‘The occurrence of a pituitary tumor, FIGURE 4. Colleagues at Mayo Clinic, Rochester, Minnesota,
who described the syndrome of parathyroid, pituitary, and
islet-cell adenoma and parathyroid tumor in the same patient is
pancreatic islet cell adenomas. A, Laurentius O. Underdahl
extremely rare. It is the primary purpose of this paper to (1907–1997), endocrinologist. B, Lewis B. Woolner, surgical
present the total Mayo Clinic experience with cases of this pathologist (emeritus professor). C, B. Marden Black (1910–
syndrome.’’ Two of the patients had duodenal ulceration and 2 1997), surgeon.
others had diffuse gastric polyposis. Five of the 8 patients had
at least 1 family member with symptoms or abnormal
biochemical or pathologic findings similar to those of the
patients in the report (Table 2). At the time, the significance Mayo Clinic that one began to recognize the syndrome as
of the intestinal disorders and the likely familial and genetic a very peculiar disorder which merited the interest of clinicians
nature of the syndrome escaped the authors. Twenty years and pathologists. In reading this article, one is impressed to
later (1973), Wermer82 commented on the Underdahl et al find cases in which the hereditary origin is evident and it seems
article: remarkable to us today that this completely escaped the
[‘‘It was only in 1953 when an excellent clinical and attention of the authors. Genetics was not yet popular with
pathological description of the adenomatosis was published by clinicians in 1953’’.]

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TABLE 2. Findings in Primary Relatives of 5 Patients With Adenomas of the Parathyroid Glands,
Pituitary Gland, and Pancreatic Islets74
Case No.
1 Sister had spells of confusion and died after a week in coma.
2 Three uncles and 1 aunt had diabetes mellitus.
3 Sister and their father had peptic ulcer.
4 Father died during surgery for peptic ulcer. Patient’s twin brother had renal calculi, and carcinoma of the pancreas
was found at autopsy.
6 Father had 3 operations for duodenal ulcer. Two uncles each died of a ‘‘brain tumor’’; both were massively obese, and 1
was possibly acromegalic. A sister was ‘‘getting fatter,’’ and a ‘‘pancreatic tumor’’ was suspected.
DOMINANT INHERITANCE OF THE
ASSOCIATION OF PITUITARY, PARATHYROID,
AND PANCREATIC ISLET CELL ADENOMAS
(FAMILIAL MEN 1)
In 1954, Wermer81 (Fig. 5) concluded that the tumor
combination enunciated by Underdahl et al was a genetic
disorder. He considered three etiologic possibilities to explain
the development of combinations of the three tumors in 5
members of a family: chance occurrence, an environmental
causative agent, and a genetic factor. He concluded ‘‘that we
are dealing here with an example of dominant hereditary
transmission and it appears probable that one autosomal
dominant gene (with high penetrance) is responsible for the
whole pathologic picture.’’ Subsequently, the association of
tumors was variously referred to as Wermer syndrome,
multiple endocrine adenomatosis, multiple endocrine adeno-
pathy, pluriglandular syndrome, and pluriglandular adenoma-
tosis; today, it is known as multiple endocrine neoplasia 1
(MEN 1).
FIGURE 5. Discoverer of the dominant inheritance syndrome of
parathyroid, pituitary, and pancreatic islet cell adenomas. Paul
Wermer (1899–1978), physician, College of Physicians and
Surgeons, Columbia University, and Presbyterian Hospital,
New York, NY. Reproduced by permission from the Columbia-
Presbyterian Medical Center, New York.
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Familial Multiple Endocrine Neoplasia
Findings
The earliest reference I found to the syndrome was
a comment by Albright and Reifenstein in their 1948 book on
the parathyroid glands and metabolic bone disease1: ‘‘This
academically most interesting but as yet inexplicable inter-
relationship between pituitary, parathyroid and islet tissues was
brought to the authors’ attention by our colleagues at Mayo
Clinic [Kepler, Rynearson, Sprague, and Keating (1947)].’’
Thus, MEN 1 was well recognized at Mayo Clinic a number
of years before the Underdahl et al article.
Initial Pathologic Terminology in MEN 1
‘‘Adenomas’’ was the general pathologic term used by
Underdahl et al74 to describe the tumors in their patients. They
also described ‘‘islet-cell adenomatosis’’ that was character-
ized by multiple circumscribed nodular areas in the pancreas,
ranging in size from giant islet-cell-like clusters to islet-cell
adenomas that were 1.5 cm in diameter. For the parathyroid
tumors, they used the terms ‘‘multiple adenomatous foci,’’
‘‘adenomatosis,’’ and ‘‘nodular hyperplasia’’ synonymously.
These terms all had a benign connotation and did not account
for 1 of the patients having an islet cell carcinoma with
metastasis and a second having a bronchial ‘‘adenoma’’
(carcinoid tumor) that also metastasized. Wermer81 used the
term ‘‘adenomatosis’’ to describe the multiple endocrine
tumors in his patients.
General Features of MEN 1
In1964, Ballard et al4 described the findings in 85
patients with MEN 1, including 11 in 6 generations of 1
family. Hyperparathyroidism was the commonest manifesta-
tion of the syndrome, affecting almost 90% of the patients. It
was caused by multiple adenomas or hyperplasia of the
parathyroid glands in more than half of the patients. Eighty
percent of the patients had at least 1 pancreatic islet tumor; two
thirds had peptic ulceration (likely due to the Zollinger-Ellison
syndrome91), one third had hyperinsulinism, and a few patients
had watery diarrhea (probably caused by a secretin-producing
islet cell tumor [Verner-Morrison syndrome]79,92). Most of the
pancreatic tumors were multifocal; one third of them were
malignant. Two thirds of the patients had pituitary tumors,
usually nonfunctioning. Some patients had adrenocortical
adenomas, adrenocortical hyperplasia, or adenomatous hyper-
plasia. Several patients had lipomas. Nearly half of the patients
died as a result of the syndrome, half of them from com-
plications of peptic ulceration, some from hypoglycemia, and
others from complications of pancreatic and pituitary tumors.
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Carney
PRIMARY PEPTIC ULCERATION OF THE
JEJUNUM ASSOCIATED WITH ISLET CELL
TUMORS OF THE PANCREAS
(ZOLLINGER-ELLISON SYNDROME)
In 1955, Zollinger and Ellison91 (Fig. 6) described 2
young patients with a syndrome of intractable gastrointestinal
tract ulceration, excessive volume of gastric secretion, and
noninsulin-producing islet cell tumors of the pancreas. The
father of 1 of the patients had died after an operation for gastric
ulcer, and the patient’s sister had died at the age of 22 years,
apparently of hyperinsulinism. In retrospect, it seems likely
that the family had MEN 1 and that the pancreatic tumors were
gastrin-secreting.
It will be recalled that several of the patients described
by Underdahl et al74 had peptic ulceration; 1 (case no. 6) had
recurrent episodes of peptic ulceration, including jejunal
FIGURE 6. Colleagues at Ohio State University, Columbus, OH,
who described the syndrome of intractable gastrointestinal
tract peptic ulceration associated with pancreatic islet cell
tumor. A, Robert M. Zollinger (1903–1992), surgeon. B, Edwin
H. Ellison (1918–1970), surgeon. Reproduced by permission
from E. Christopher Ellison, MD.
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Am J Surg Pathol  Volume 29, Number 2, February 2005
involvement, and recurrent and ultimately fatal gastrointestinal
tract hemorrhage, findings that in hindsight are suggestive of
the Zollinger-Ellison syndrome. I was recently able to
substantiate this diagnosis by showing the presence of gastrin
in 1 of the patient’s pancreatic tumors (Fig. 7).
SYNDROME OF ISLET CELL
TUMOR-ASSOCIATED REFRACTORY WATERY
DIARRHEA AND HYPOKALEMIA
(VERNER-MORRISON SYNDROME)
In 1958, Verner and Morrison79 described 2 patients
with diarrhea and hypokalemia associated with islet cell
tumors, and collected 7 similar cases from the literature. Ten
years later, Zollinger et al92 implicated secretin as the
diarrheogenic agent produced by the islet cell tumors.
MEDULLARY (SOLID) CARCINOMA OF
THE THYROID GLAND
There were rare reports of malignant goiter with amyloid
in the older German literature. Most of the cases seem to have
been due to secondary amyloidosis. In 1910, Stoffel,71 how-
ever, described the case of a 43-year-old woman with an
enlarged thyroid due to a carcinoma with amyloid; the latter
was interpreted as a manifestation of primary amyloidosis. In
1954, Brandenburg7 reported another thyroid carcinoma with
amyloid in a patient did not have generalized amyloidosis. In
this case, the metastatically involved cervical lymph nodes
also showed amyloid.
In January 1959, Hazard et al (Fig. 8)39 of the Cleveland
Clinic, Cleveland, OH, reported 21 cases of a peculiar type of
thyroid carcinoma that had a ‘‘solid nonfollicular histologic
pattern, the presence of amyloid in the stroma, and a high
incidence of lymph node metastasis.’’ The biologic behavior of
the tumor was intermediate between those of papillary
carcinoma and anaplastic thyroid carcinoma. In their landmark
article, Hazard et al39 suggested the name ‘‘medullary (solid)
thyroid carcinoma’’ for the tumor. They stated that ‘‘consider-
able thought has been given to the selection of a term that will
indicate the distinctive histologic features of the tumor.’’
Initially, they considered the term ‘‘solid’’ for the carcinoma
but felt that this might result in confusion with anaplastic
carcinoma that also had a solid growth pattern. Finally, they
settled on ‘‘medullary carcinoma’’ because ‘‘medullary’’ was
a term ‘‘commonly used for a histologically solid type of
tumor,’’ although they realized that this term connoted a soft
tumor, which MTC was not. In the end, they compromised and
included ‘‘solid’’ in the title of their article. Interestingly,
‘‘solid’’ was the descriptor for MTC in use at Mayo Clinic in
the early 1950s, and even after publication of the article by
Hazard et al in 1959, it continued to be the favored title for the
tumor there for a number of years90 and at M. D. Anderson
Hospital, Houston, TX, as late as 1967.41
I had hoped that Dr. Hawk might have an interesting
anecdote about the discovery of MTC to interest readers, but
he didn’t. Still, he came up with a winner by telling me about
one of Hazard’s extracurricular interests. Dr. Hawk recalled:
The surgical pathology labs (at the Cleveland Clinic) were
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FIGURE 7. Immunostaining of differ-

ent pancreatic islet tumors from case
no. 6 of Underdahl et al in 1953
(staining performed in 2003). A, A few
cells are positive for insulin. B, About
half of the cells are weakly positive for
glucagon. The appearances are con-
sistent with nesidioblastosis. C, A few
cells are positive for somatostatin. D,
Cells are positive for gastrin.

a crowded place so that the comings and goings of the staff and
residents were easy to observe. One thing we knew about
Beach Hazard was he never took lunch but every day took
a walk, always in the same direction, apparently to the same
destination. We residents were curious about the behavior and
so decided to follow him. At a discreet distance, we followed
him eastward on Chicago Avenue and then down 105th street
to a sordid looking news store where he entered. He emerged 5
minutes later with a copy of the Racing Form. He walked
straight back to the Clinic. We were never certain if he knew
we had followed him. Subsequently, he gave us some friendly
advice. ‘‘Never wager on a horse to win, always wager to place
or show.’’
Dr. Hawk recalled a second and related anecdote: When
Hazard retired, he moved to Key Biscayne, FL. He bought
a box at the Hialeah Race Track and spent as many afternoons
as possible wagering on the horses. Between races, he busied
himself by working on some papers he was writing. One day
he was particularly busy working over some galley proofs. A
young lady in an adjoining box was intrigued by the mixture of
intense interests. She introduced herself as the society editor
for the Miami Herald and asked if he would agree to an

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Carney
FIGURE 8. Colleagues at the Cleveland Foundation, Cleveland,
OH, who described medullary (solid) carcinoma of the thyroid.
A, J Beach Hazard (1905–1994), pathologist. B, William A.
Hawk, pathologist (emeritus clinical professor). C, George C.
Crile, Jr (1907–1992), surgeon.
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Am J Surg Pathol  Volume 29, Number 2, February 2005
interview. Several weeks later, the interview was published. Its
title was ‘‘Thyroid by a Neck.’’
Bilateral Solid Carcinoma of the Thyroid,
Bilateral Pheochromocytoma, and
Ganglioneuromatosis, Possibly
Familial (MEN 2B)
In June 1959, when she was 7 months pregnant, the
patient who was the 14-year-old girl described earlier seen at
Mayo Clinic in June 1952 with ‘‘solid nonpapillary thyroid
carcinoma’’ had massive vaginal bleeding caused by placenta
previa. During emergency cesarean section, she had fatal
cardiovascular collapse. Autopsy findings included bilateral
pheochromocytoma and metastatic MTC to the lungs, lymph
nodes, and liver. Histologic sections from the autopsy were
sent to the late Dr. Malcolm Dockerty at Mayo Clinic for his
impression. The closing paragraph of his letter to the
submitting pathologist read: ‘‘I have never seen the combi-
nation of pheochromocytoma with thyroid cancer. Can it be
that we have discovered still another example of different
cancers simultaneously involving two or more ductless
glands—bilaterally, if you please?’’ Dr. Dockerty had done
just that—encountered an undescribed syndrome. ‘‘Another
example’’ undoubtedly referred to the pituitary, parathyroid,
and pancreatic tumor combination with which he was
familiar.52 But he did not follow up his hunch and search
for similar cases. If he had, he likely would have found the
reported cases of pheochromocytoma: carcinoma of the
thyroid association that Sipple66 uncovered 2 years later. An
opportunity was missed.
The patient’s premature daughter died at age 17 days. At
autopsy, there was ‘‘marked absence of subcutaneous fat.’’
There were no thyroid (Fig. 9) or adrenal tumors. The
abdomen was protuberant because of marked dilatation of the
small bowel. The main microscopic finding in the intestine of
both mother and daughter was a diffuse ganglioneuromatosis
(Fig. 9). The occurrence of this very rare neural pathologic
finding in first-degree relatives, 1 a premature infant,
suggested the likelihood of a transmissible trait and raised
the possibility that the mother’s tumors, pheochromocytoma
and MTC, might also be heritable and part of a syndrome.
Later, alimentary tract ganglioneuromatosis was shown to be
a major component of the MEN 2B syndrome.13
ASSOCIATION OF PHEOCHROMOCYTOMA
AND CARCINOMA OF THE THYROID
GLAND (MEN 2)
In April 1959, Sipple66 (Fig. 10), then a 29-year-old
third-year medical resident, encountered a 33-year-old, pre-
viously normotensive man with unexplained fluctuating
hypertension. The patient suffered several intracerebral
hemorrhages and died after decompression craniotomies.
Dr. Sipple told me that he assisted at the patient’s postmortem
and ‘‘was astounded by the findings of bilateral pheochromo-
cytoma, bilateral carcinoma of the thyroid gland, and
a parathyroid adenoma.’’ He thought the findings ‘‘were very
strange—there must be something going on.’’ Curious and
seeking an explanation for the bilateral tumors in two
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FIGURE 9. Ganglioneuromatosis in
MEN 2B. A, Hypertrophied nerve with
ganglion cells in bronchial submucosa
of a 20-year-old woman. B, Nerve
with ganglion cells in the thyroid of
the 20-year-old patient’s premature
daughter (7 months’ gestation). (It is
very unusual to see nerve or ganglion
cells in normal thyroid.)
endocrine organs in his case, Sipple searched Index Medicus
for cases of pheochromocytoma and found 537. A thyroid
carcinoma was reported in 5 of the 537 (Table 3). The
histologic subtype was not uniform.
In the ‘‘Discussion’’ section in his article, Sipple stated:
‘‘Although the overall incidence of malignancy of other organs
is not increased in pheochromocytoma, the incidence of
carcinoma of the thyroid is increased far beyond expectations
based on chance occurrence.’’ He calculated that the incidence
of thyroid carcinoma in patients with pheochromocytoma was
increased 14 times beyond that in the general population.
Later, the combination of pheochromocytoma and thyroid
carcinoma was commonly referred to as Sipple syndrome.43
Sipple’s inquisitiveness paid off.
Sipple did not mention whether a parathyroid tumor had
occurred in any of the 5 patients with pheochromocyoma and
thyroid carcinoma he had found in the literature. Wondering
about this, I reviewed the original reports of the cases and
found no mention of parathyroid disease. But it is hardly
coincidental that 1 of the 530 had a sister who also had
a thyroidectomy and died at the age of 28 years, with clinical
findings strikingly similar to those of the patient herself and
which were believed to have been caused by ‘‘a rare
disturbance of the sympathetic system.’’
Doubtless because Sipple had not illustrated his patient’s
carcinoma and because of their suspicion that the tumor might
be MTC, Schimke et al65 reviewed the histology of the tumor
(initially interpreted as follicular type) in 1968 and reinter-
preted it as MTC. Later, I obtained the autopsy slides from the
case and demonstrated the presence of calcitonin in the tumor
(Fig. 11). Of interest was the presence of previously un-
mentioned enlarged nerves reminiscent of those seen in MEN
2B, in the pancreatic septa and the periadrenal fat (Fig. 12).
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However, the patient has no microscopic evidence of
alimentary tract ganglioneuromatosis, and Sipple told me that
he had a normal appearance. An overlap in expression of MEN
2A and MEN 2B might explain this neural abnormality.73 Not
all patients with the neuroma phenotype have obviously
abnormal lips and eyelids,24,25 indicating that the neural
lesions develop to a greater degree in some patients than in
others. Such variability might explain the enlarged pancreatic
and periadrenal nerves in Sipple’s patient. Molecular genetic
studies might have provided further information on this point,
but the tissue blocks were discarded.
In reviewing the original reports of the 5 cases of
pheochromocytoma and thyroid carcinoma that Sipple found
in the literature, I noticed that 1 patient (Sipple’s case no. 6)
had prognathism,22 an abnormality that may occur as part of
the neuroma phenotype. Wondering whether this might be a
clue that the patient had MEN 2B, in the mid 1970s I obtained
a summary of the clinical record, the autopsy protocol, and the
histologic slides from the 1954 autopsy. The latter showed that
the thyroid carcinoma was MTC and not anaplastic carcinoma
as originally reported, and also that the patient had alimentary
tract ganglioneuromatosis. A photograph showed the patient’s
irregularly enlarged lips (Fig. 13). Additionally, there were
a series of skeletal and dental abnormalities. The totality of the
findings indicated that the patient had MEN 2B. To my
knowledge, this case may be the first report of the full MEN 2B
syndrome (the specific endocrine tumors and the neuroma
phenotype), albeit without the important clinical and patho-
logic details just mentioned but with a clue to the syndrome,
prognathism.
Thus, it turns out that the 5 cases that Sipple found in the
literature included 1 with MEN 2B and a second likely with
MEN 2A.
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BILATERAL PHEOCHROMOCYTOMA,
MULTIGLAND PARATHYROID DISEASE,
AND BILATERAL MTC
The index patient of the trio with bilateral pheochro-
mocytomas who attended Mayo Clinic in 1951 returned to
Mayo Clinic in September 1961. Her blood pressure was
190/115 mm Hg. Pharmacologic tests were again positive for
pheochromocytoma. Excretory urography showed bilateral
nephrocalcinosis. Abdominal exploration revealed recurrent
right-sided pheochromocytoma. Serum concentrations of
calcium measured postoperatively ranged from 3.20 to 3.52
mM (reference range, 2.22–2.52 mM). A diagnosis of primary
hyperparathyroidism was made. Cervical exploration dis-
closed four abnormal parathyroid glands that contained
multiple adenomas (Fig. 14A–C). Also found were bilateral
occult solid carcinomas with amyloid stroma (Fig. 14D).
The report53 of the evolution of this case including disease of
all four parathyroid glands provided the first full description
of the complete MEN 2A syndrome. In 1966, the patient
had bilateral local recurrences of the pheochromocytomas and
also hepatic metastases. She died of metastatic pheochromo-
cytoma in December 1999. The patient had 2 children, 1 of
whom was affected and passed the MEN 2A trait to 2 of her
children.
The previous patient’s sister had another operation for
symptoms of pheochromocytoma in 1965; hepatic metastasis
was found. Two years later, she underwent total thyroidectomy
for bilateral MTC; during the operation, two parathyroid
adenomas were found.59 The patient was well at age 80 years
in 2003.
Their brother returned to Mayo Clinic in 1965 and had
an operation for bilateral MTC. He returned again in 1995 for
treatment of cervical lymph node metastases. Aware of his
nickname ‘‘Shakey,’’64 I could not resist visiting him in the
hospital to see his reaction to it. There was a blank look of
puzzlement on his face. I was embarrassed. I had to explain
how I had learned about his nickname. Briefly, he showed
some irritation—not with me, fortunately, but with his mother.
It was she, he said, who had provided his nickname and its
origin to his physicians, not he. It was not something that he
would have volunteered, he assured me. He was alive and well
in 2003.
In 1962, Cushman19 reported cases of MTC in 3 patients
in three successive generations of a family. The first patient
also had pheochromocytoma and a parathyroid adenoma, the
second also had pheochromocytoma, and the third had MTC
only. The findings suggested that the MEN 2A syndrome was
transmitted as an autosomal dominant trait with varying
degrees of penetrance.

FIGURE 10. Investigators of MTC. A, John H. Sipple,

pulmonologist (emeritus clinical professor), State University
of New York Upstate Medical Center, Syracuse, NY. B, Sir E.
Dillwyn Williams, pathologist (emeritus professor), Baron
Institute of Pathology, London University, London, United
Kingdom. C, A. G. Everson Pearse (1916–2003), pathologist
and histochemist, Royal Postgraduate Medical School, Ham-
mersmith Hospital, London, United Kingdom.

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TABLE 3. Five Cases of Pheochromocytoma and Thyroid
Carcinoma Collected by Sipple From the Literature66
Case Age Thyroid
No. (yr) Sex Carcinoma Pheochromocytoma Reference
II 63 F Papillary Bilateral
III 17 M Adenocarcinoma Unilateral
IV 33 F Adenocarcinoma Bilateral
V 24 F Anaplastic Unilateral
VI 37 F Anaplastic* Bilateral
*Review of histologic findings showed MTC.
MULTIPLE MUCOSAL NEUROMATA,
MTC, AND PHEOCHROMOCYTOMA
CONSTITUTE A SYNDROME ALLIED TO
VON RECKLINGHAUSEN’S
NEUROFIBROMATOSIS (MEN 2B)
In the mid 1960s, E. Dillwyn Williams (Fig. 10B) made
a series of major contributions to the histogenesis, pathology,
and syndromic associations of MTC. First, in 1965, in a review
of 17 cases of carcinoma of the thyroid and pheochromocy-
toma,84 he noted that the latter was frequently bilateral and
familial, and that the thyroid carcinoma was usually MTC.
In 1966, Williams and Pollock88 described oral mucosal
and eyelid neuromas, MTC, pheochromocytoma, and diffuse
ganglioneuromatosis of the alimentary tract in 3 patients
(2 who were father and daughter) and concluded that
the combination constituted a neuroectodermal syndrome,
closely allied to von Recklinghausen neurofibromatosis. von
Recklinghausen neurofibromatosis is 1 of a small group of
conditions, including von Hippel-Lindau disease and tuberous
sclerosis, that van der Hoeve76 had grouped together in the mid
1920s under the designation ‘‘phakomatoses.’’ The disorders
were familial and featured skin abnormality, true tumors and
hamartomas, congenital abnormalities, and occasionally
endocrine tumors. It is possible, likely perhaps, that van der
Hoeve would have included the neuroma phenotype in the
group, had he been aware of it.
The mucosal neuroma disorder has been called the
Wagenmann-Froboese syndrome56 and the Froboese syn-
drome,77 in recognition of the authors of the first separate
descriptions of the facial appearance of patients with the
syndrome, and also Sipple syndrome63 (incorrectly, because
Sipple’s patient did not have the neuroma phenotype, as has
been mentioned). Arguably, Williams was at least as deserving
as Froboese and Wagenmann of having his name eponymically
associated with the syndrome because it was he who first made
the important connection between the abnormal phenotype,
and MTC and pheochromocytoma. Recently, he was knighted
for his contributions to pathology.
At least nine references to the neuroma pheno-
type8,24,31,42,47,51,55,75,80 had been published commencing in
1922, before Williams and Pollock88 connected it with
endocrine tumors. The titles of most of the articles suggested
that it was most likely a neural disorder, less likely
a gastrointestinal tract one. In 1968, Gorlin et al36 reviewed
14 apparently sporadic cases of the syndrome collected from
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the literature, and later Gorlin and Mirkin35 suggested
a unitarian concept to explain the syndrome based on
hyperplasia and neoplasia of neural crest derivatives.
26 MEDULLARY CARCINOMA IS THE ONLY
6 THYROID CARCINOMA ASSOCIATED WITH
58 PHEOCHROMOCYTOMA
30 In 1966, Williams et al85 concluded that MTC was the
22 only type of thyroid carcinoma associated with pheochromo-
cytoma. In a companion article, Williams86 suggested that
MTC was of parafollicular cell origin, based on the histologic
similarity of the human tumor to a thyroid tumor in dogs and
rats, thought to be of parafollicular cell origin. Parafollicular
cells were so named because they lay between the thyroid
follicular cells and the basement membrane. They had clear
cytoplasm and were easily identified in laboratory animals but
difficult to see in humans. Their function was unknown. In the
following year, Bussolati et al9 showed that the hormone
calcitonin was localized in the parafollicular cells, and Pearse’s
group subsequently demonstrated that calcitonin was present
in MTC.10 Williams87 later presented a classification of the
syndromes associated with MTC (Fig. 15). In 1968, Melvin
and Tashjian54 showed that the serum level of calcitonin was
elevated in patients with MTC.
AMINE PRECURSOR UPTAKE AND
DECARBOXYLATION CONCEPT
From the work of Pearse61 (Fig. 10C) emerged the
possibility in the late 1960s that there might be an actual or
potential developmental relationship between the different
cells of the various endocrine organs mentioned earlier
(pituitary, parathyroid, pancreatic islet, thyroid parafollicular,
and adrenal medullary) and the central nervous system. Pearse
identified cells in a group of endocrine glands with common
cytochemical and functional attributes, specifically, amine
content or amine precursor uptake and decarboxylation
(APUD) or both. Identification of cells with similar properties
in the neural crest and the results of embryologic tracer studies
led to the suggestion that most, if not all, of the syndromic
endocrine tumors were of neural crest origin and to the intro-
duction of new terms for their tumors, including apudoma,
neurolymphoma, and neurocristoma.60 Within a decade of its
introduction, the term ‘‘APUD’’ was in wide use. However,
Pearse’s concept was criticized, and changes were made in it to
accommodate new findings, new constituents, and certain
justified objections.2
INTRODUCTION OF THE TERM
‘‘MULTIPLE ENDOCRINE NEOPLASIA’’
As mentioned earlier, Steiner et al70 (Fig. 16A)
introduced the term ‘‘multiple endocrine neoplasia’’ in
1968. Their purpose was to 1) designate a new disease
category composed of combinations of endocrine tumors, 2)
emphasize the separateness of the Wermer and Sipple
syndromes, and 3) facilitate classification of undiscovered
endocrine tumor combinations. The classification included
combinations of tumors that were familial (MEN 1 and MEN
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FIGURE 11. MTC and parathyroid

adenoma from Sipple’s case.66 A,
Panoramic view of a partially circum-
scribed but invasive, fibrotic and
focally calcified tumor. B, Hematoxy-
lin and eosin-stained section from
1975 was destained and restained
with anti-calcitonin antiserum in
2003 and shows positive staining of
the tumor. Extratumoral perifollicular
foci of positive cells are consistent with
C cell hyperplasia. C, Low power view
of parathyroid adenoma slightly inter-
mingled with thyroid parenchyma.
D, High power view of parathyroid
adenoma showing a sheet of well-
outlined cells with uniform nuclei and
clear cytoplasm.

2) and nonfamilial (MEN 3). Subsequently, the term ‘‘multiple
endocrine neoplasia’’ was used almost exclusively to refer to
the familial syndromes. The term ‘‘MEN type 3’’ was later
applied by some to the neuroma phenotype constellation45
(Table 1). The features of MEN 1 and MEN 2 included 1)
combinations of endocrine tumors, 2) tumor multifocality and
bilaterality in the case of paired organs, 3) autosomal dominant
inheritance, and 4) tumor synthesis and secretion of peptides
or amines.
PRECURSORS OF MTC,
PHEOCHROMOCYTOMA, AND PANCREATIC
ISLET CELL TUMORS IN THE MEN SYNDROMES
C Cell Hyperplasia
In 1973, Wolfe et al89 detected small but progressively
larger, abnormally high serum concentrations of immunore-
active calcitonin in response to calcium infusion in 2 sisters at
risk for familial MTC. Thyroidectomy was performed in both

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FIGURE 12. Probable neural abnor-
mality in Sipple’s case.66 A, Large
nerves in septa between pancreatic
lobules. B, Enlarged nerve with sug-
gestive neuromatous appearance just
outside the adrenal capsule (space
between nerve and capsule is artifac-
tual).
cases. Neither patient had grossly visible tumor, but
microscopically both had a marked multifocal increase and
clustering of noninvasive calcitonin-containing cells in the
middle and upper portions of the lateral lobes. The finding was
interpreted as C cell hyperplasia (Fig. 17), a preinvasive or
hyperplastic process that was deemed to be the precursor of
familial MTC.
Adrenal Medullary Hyperplasia
In 1972, Ljungberg49 reported diffuse thickening of the
adrenal medulla accompanied by nodules of pheochromocy-
toma up to 0.5 cm in diameter in 2 cases of MEN 2. In 1976,
Carney et al15 and DeLellis et al23 described hyperplasia of
the adrenal medulla in MEN 2 characterized by a reversal of
the normal corticomedullary ratio, extension of the medulla
into the tail and alae of the glands, and development of
unencapsulated nodules in the zones of hyperplasia (Fig. 17).
The changes were presumed to be precursors of the syndromic
pheochromocytoma.
Nesidioblastosis
Recently, nesidioblastosis, a proliferation of small ducts
and budding-off of endocrine cells from duct epithelium, was
found in the pancreas of patients with MEN 13,46 (Fig. 17). It
will be recalled that Cushing and Davidoff18 mentioned that
the pancreatic islets in their case of probable MEN 1 were
unusually large and possibly increased in number. Lloyd50 also
had commented that the islets were unusually large in his
similar case.
GENERAL FEATURES OF MEN 2
In 1972, Ljungberg49 reported the cases of 114 patients
with MEN 2A from 22 affected families. Fifty-nine patients
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(52%) had MTC and pheochromocytoma, 30 (26%) had MTC
only, 25 (22%) had pheochromocytoma only, and 3 (3%) had
parathyroid disease.
In the following year, Keiser et al44 studied 256 members
of 5 generations of an affected family. Twenty-five individuals
had MTC, 11 pheochromocytoma, 16 parathyroid disease, and
6 all 3 conditions. The mean ages at diagnosis of each
condition were 31 years for MTC, 35 years for pheochromo-
cytoma, and 34 years for parathyroid disease. Of 24
individuals who had an operation for MTC, 21 (84%) were
alive (follow-up was less than 3 years in half of the cases) and
3 were dead of metastatic MTC. The pheochromocytoma was
bilateral in 7 patients; none of the tumors gave rise to
metastasis. Parathyroid disease with evidence that was clinical
or pathologic, or both, was present in 16 patients (64%). The
parathyroid glands were hyperplastic in 12 patients and
hypercellular in 4.
In a review of 66 cases of MEN 2A from 7 affected
kindreds, Sizemore et al68 found that all patients had MTC, 14
(21%) had MTC and parathyroid disease, 8 (12%) had MTC
and pheochromocytoma, and 5 (7%) had MTC, pheochromo-
cytoma, and parathyroid disease. Most of the patients
presented with a thyroid nodule or enlarged cervical lymph
nodes. Sixty-five percent of the patients were apparently cured.
Metastatic MTC was found at primary surgery in 23% of the
patients. No patient had died of metastatic MTC at 5-year
follow-up.
Ironically, each of the 3 members of the first family with
MEN 2A seen at Mayo Clinic64 described earlier presented
with large bilateral functioning pheochromocytomas (sub-
sequently metastatic in 2), and only more than a decade later
did MTC (occult) and parathyroid disease appear in a member
of the family.
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FIGURE 13. Reported case of pheochromocytoma from De
Graeff et al.22 The patient had markedly thickened lips,
abnormal dentition, and a broad nose.
CHROMOSOMAL MAPPING AND MOLECULAR
GENETICS OF THE MEN 1 AND
MEN 2 SYNDROMES
MEN 1
The chromosomal site of the genetic defect in MEN 1
was localized by Larsson et al48 in 1988 by demonstrating
linkage of the disorder to the centromeric region of the long
arm of chromosome 11 (11q13). Subsequently, Chandra-
sekharappa et al16 identified the MEN 1 gene whose protein
product, termed menin, had no apparent similarity to any
known protein.
MEN 2A and MEN 2B
These conditions are allelic disorders caused by muta-
tions of the RET gene.28 In 1993, Gardner et al34 using genetic
linkage studies mapped MEN 2 loci to a small interval on
chromosome 10q11.2. In the same year, Mulligan et al57
identified missense mutations on the RET protooncogene in 20
of 23 MEN 2A families. In 1994, Hofstra et al40 demonstrated
a mutation in codon 918 of the gene in MEN 2B that resulted
in substitution of a threonine for a methioinine in the tyrosine
kinase domain of the RET protein.
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MEN SYNDROMES AND NONENDOCRINE
CONDITIONS
As has been intimated, the three currently accepted
familial MEN syndromes are MEN 1, MEN 2A, and MEN 2B.
In 1968, when Steiner et al70 introduced the term ‘‘multiple
endocrine neoplasia,’’ endocrine tumors were the only
disorders included in the disease category. In 1973, Sizemore
et al (Fig. 16B)67 expanded the ‘‘multiple endocrine neo-
plasia’’ category by including in it a group of nonendocrine
conditions, specifically, the neuroma phenotype. The sugges-
tion and rationale behind it were included in an article (Fig. 18)
that was submitted for publication in the American Journal of
Medicine. The manuscript was returned to the authors for
revision, but it was never revised or published. The
‘‘Introduction’’ section in the manuscript stated in part:
n Multiple endocrine neoplasia, type 2 (MEN type 2) is
a designation proposed by Steiner et al70 in 1968 for the
association of medullary thyroid carcinoma, pheochromocy-
toma, and parathyroid disease in patients with normal
appearance. Wagenmann, in 1922, reported the case of
a 12-year-old boy with neuromas on the eyelids and tongue.
Fifty-five similar patients (including our 7) have been
reported. Sufficient differences exist between these patients
and those reported by Steiner et al to warrant a new
designation. We propose the designation ‘‘multiple endocrine
neoplasia, type 2b’’ (MEN type 2b) for patients with somatic
abnormalities including multiple mucosal neuromas and
prominent corneal nerves in addition to medullary thyroid
carcinoma or C-cell hyperplasia and pheochromocytoma.
The 7 patients mentioned by Sizemore et al67 were
members of 3 generations of a family in which MEN 2B was
transmitted as an autosomal dominant trait.
CLINICAL IMPORTANCE OF THE NEUROMA
PHENOTYPE
When Sizemore realized that the neuroma phenotype
was associated with specific endocrine tumors and that the
combination could be familial, he wrote a letter of inquiry to
the father of the girl born in 1956 whose mother was the
deceased patient mentioned earlier in this article who had
come to Mayo Clinic in 1947. The following response came
from the daughter’s concerned stepmother:
n Just found this letter. Our mail out here isn’t the best—I
knew B’s first wife very well and know what she looked like.
She is 17 years old now. She is exactly like her mother (Fig.
3B). She has the large lips, which we had operated on so it
wouldn’t be so bad. She also has the eyelids and tongue like
you said. Her health is excellent but she is skinny as a rail. She
has a leg that is shorter. Anything that should be done for her
that we should do, please let us know.
The daughter was initially thought to have had ‘‘an
imperforate anus,’’ then Hirschsprung disease; a rectal biopsy,
however, showed many nerves and ganglion cells (ganglio-
neuromatosis). She was a ‘‘floppy infant’’ and had never teared
when she cried (possibly an extreme form of the ‘‘dry eye’’
symptoms that are common in MEN 2B). When examined at
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FIGURE 14. First reported case of complete MEN type 2A.53 A, Cystic, collapsed right superior parathyroid adenoma. B, Excised
portion (0.2 g) of left superior adenoma showed a sheet of clear cells and a rim of the parent gland. C, Left inferior parathyroid
adenoma (0.5 g) composed of clear and dark cells. D, Bilateral MTC in the upper poles of the thyroid. The right inferior parathyroid
gland (shown) measured 2 3 1.5 3 0.8 cm and weighed 1.25 g. Reproduced with permission.53 E, Recent immunostaining of the
thyroid tumors with anti-calcitonin antiserum showed positive staining.

Mayo Clinic in 1973, she was 155 cm tall and had a span of
162 cm. She weighed 35 kg. She had marked dolichocephaly.
There were small neuromas on both lower eyelids. Thickened
corneal nerves were visible with the naked eye (usually slit-
lamp examination of the cornea is necessary to make this
observation). The lips were thickened despite the prior plastic
surgery. There were multiple neuromas on the free margin of
the tongue, on the inner surfaces of the lips, and on the buccal
mucosa. The palate was tall and narrow. The digits were long
and slender, and joint laxity was increased. There was marked
upper thoracic kyphosis and lower thoracic scoliosis, bilateral
coxa valga, and bilateral pes planus. The right lower limb was
4 cm shorter than the left. Nodules were palpable in both lobes
of the thyroid, and regional lymph nodes were enlarged and
hard. Calcitonin and catecholamine studies and localization
techniques revealed the presence of MTC and pheochromo-
cytoma. The serum calcium level was normal. Total
thyroidectomy was performed for bilateral MTC, and bilateral
adrenalectomy for bilateral pheochromocytomas. Postopera-
tively, the serum calcitonin level remained elevated.
The patient died in 2001 at age 45 years not of metastatic
MTC, which was already present at age 17 but of malnutrition,
the result of ‘‘achalasia’’ of the esophagus that had caused
progressive inability to eat or drink, and which presumably
was due to esophageal ganglioneuromatosis.20
This case may be the first instance in which suspicion of
the hereditary nature of the neuroma phenotype led to
investigation of an at-risk family member.

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Carney
FIGURE 15. Familial syndromes associated with medullary
carcinoma of the thyroid as presented by Williams in 1966.
Reproduced with permission.87
MEN 2A AND MEN 2B
In 1975, Chong et al17 provided the logical expansion of
the Sizemore et al 1974 MEN 2B terminology by suggesting
that Steiner et al’s MEN, type 2 disorder category (MTC,
pheochromocytoma, and parathyroid adenomas) be retitled
‘‘multiple endocrine neoplasia Type 2A (MEN Type 2A)
(Table 1).
In 1989, Gagel et al on behalf of the Organizing
Committee of the Third International Workshop on Multiple
Endocrine Neoplasia Type 232 recommended that Sizemore’s
terminology be emended to MEN 2A (from MEN, type 2A)
and MEN 2B (from MEN, type 2B) (Table 1). These titles are
now the preferred ones for the syndromes.
Familial Multiple Endocrine Tumors
and Other Associated Conditions
The addition of the neuroma phenotype as a component
of a familial MEN syndrome accepted that a nonendocrine
condition could be a major or even clinically dominant
component of a familial MEN syndrome. Subsequently,
several candidate MEN syndromes were reported, some with
nonendocrine components and others without (Table 4). In
1980, Carney et al12 described 2 patients, a young woman (the
propositus) and her mother with pheochromocytoma(s) (a
component of MEN 2) and a pancreatic islet tumor (a
component of MEN 1). This was apparently a new familial
endocrine tumor combination and appeared to be a new MEN
syndrome. The case for this was supported by observations in
2 other families of Mayo Clinic patients, a member of 1 of
which also had findings suggestive of neurofibromatosis, and
by 7 prior reports of the pheochromocytoma-islet cell tumor
association. In 5 of the latter, the patients or their families had
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Am J Surg Pathol  Volume 29, Number 2, February 2005
FIGURE 16. Devisers of the classification scheme for MEN
syndromes. A, Alton B. Steiner, endocrinologist (clinical
professor), Christus St. Joseph Hospital, Houston, TX. B, Glen
W. Sizemore, endocrinologist (emeritus professor), Mayo
Clinic, Rochester, MN, and Loyola University, Chicago, IL.
von Hippel-Lindau disease or findings suggestive of this
disorder.
In 1997, follow-up of the mother and daughter in the
Carney et al report12 disclosed that one of the daughter’s 2 sons
had multiple intracranial and intraspinal hemangioblastomas
(a component of von Hippel-Lindau disease) and café-au-lait
spots and a meningioma (both of which are findings common
in neurofibromatosis). The second son had pheochromocyto-
ma, a neoplasm that may complicate von Hippel-Lindau
disease and also neurofibromatosis. What disorder the family
had was unclear. It could have been MEN 3 manifested by a
new familial combination of neoplasms, pheochromocytoma,
and islet cell tumor, as was implied by Carney et al12 in 1980
that later, by chance, had manifested findings suggestive of
von Hippel-Lindau disease and possibly neurofibromatosis
(both nonendocrine conditions) in 1 of its members. But this is
not very likely. A more plausible explanation is that the family
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Am J Surg Pathol  Volume 29, Number 2, February 2005 Familial Multiple Endocrine Neoplasia

FIGURE 17. Presumed precursors of medullary thyroid carcinoma, pheochromocytoma, and islet cell tumor. A, C cell hyperplasia
characterized by clusters of polygonal to spindle-shaped cells with clear to faintly acidophilic cytoplasm, in parafollicular location.
B, Immunofluorescent staining for calcitonin in the parafollicular cells in A. (A and B, reproduced with permission.89). C, Bilateral
diffuse and nodular adrenal medullary hyperplasia manifested by diffuse expansion of the medulla with multiple nodules up to 5
mm in diameter. D, Diffuse and nodular medullary hyperplasia in the gland illustrated in C. There is a massive increase in the size of
the medulla with preservation of the general shape of the gland. A nodule is present in the expanded medulla (nodular medullary
hyperplasia). (C and D, reproduced with permission.15). E and F, Case no. 6 in Underdahl et al.74 Nesidioblastosis characterized by
the presence of isolated insulin-positive cells in the pancreatic parenchyma and duct (with budding of the cells).

had von Hippel-Lindau disease combined with neurofibro-
matosis, manifested in the majority of the affected members
by pheochromocytoma and pancreatic islet cell tumor.
Whatever the correct explanation of the family’s disorder
was, the findings provided more evidence of a connection be-
tween nonendocrine conditions (the neuroma phenotype, von
Hippel-Lindau disease and neurofibromatosis) and the familial
MEN syndromes.
In 1985, Carney et al14 described another disorder (the
Carney complex) that featured multiple endocrine tumors, non-
endocrine conditions, and an autosomal dominant inheritance
pattern. The endocrine conditions were primary pigmented

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Carney
FIGURE 18. Title page of the 1974 manuscript by Sizemore
et al that introduced ‘‘multiple endocrine neoplasia type 2B’’
terminology. Submitted for consideration for publication to
the American Journal of Medicine in November 1974.
nodular adrenal disease and pituitary adenoma (some male
patients also had steroid-type testicular tumors). The disorder
could qualify as a familial MEN syndrome because it 1)
featured a combination of endocrine tumors not previously
described, 2) displayed the expected tumor pattern (multi-
focality; bilaterality in the affected paired organs [the adrenals
and testes]), and 3) was familial. The disorder also had
nonendocrine conditions (lentigines and myxomas), and
resembled MEN 2B in that the presenting features were
usually the nonendocrine conditions. The frequency of the
individual components had the following frequencies among
affected patients with the Carney complex: lentigines, 77%;
myxomas, 53%; endocrine tumors, 30%; and schwannomas,
10%.72 The type and frequency of these components suggest
that the Carney complex could be interpreted as a lentiginosis
syndrome, with similarities to the Peutz-Jeghers syndrome.
These observations indicate that a nomenclature may be
TABLE 4. Selected Candidate Familial MEN Syndromes
Nonendocrine
Endocrine Tumors Inheritance Component
Pheo Islet cell AD VHL
Duod carcinoid Pheo VRNF
Duod carcinoid Pheo VHL
Pheo, pheochromocytoma; AD, autosomal dominant; VHL, von Hippel-Lindau disease; duod, duodenal; VRNF, von Recklinghausen neurofibromatosis.
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Am J Surg Pathol  Volume 29, Number 2, February 2005
needed that will take into account (for practical reasons) the
relative contributions of endocrine and nonendocrine compo-
nents. It seems reasonable to suggest that when the non-
endocrine component(s) of a syndrome that features multiple
endocrine tumors is clearly dominant clinically, it is not logical
to label the overall condition simply as an MEN disorder.
Is There a Pure MEN Syndrome?
When examined critically, it is apparent that the classic
MEN syndromes are associated with nonendocrine conditions
to at least some extent. Even MEN 1, ordinarily not thought of
as having nonendocrine associations, occasionally features
lipomas,4 and recently, among 32 consecutive affected
patients, multiple facial angiofibromas were reported in 88%
and collagenomas in 72%.21 MEN 2A may be associated with
Hirschsprung disease78 and lichen sclerosis amyloidosis.33
Thus, each of the three accepted familial MEN syndromes is
not simply an endocrine disorder.
FUTURE DIRECTIONS FOR MEN
NOMENCLATURE
The foregoing indicates the desirability of having
a method for classifying and naming presently unknown
familial syndromes that include multiple endocrine tumors and
for deciding which merit the MEN designation and which do
not. Experience to date suggests the following approach.
First, because certain tumors in the familial MEN
syndromes are malignant, the term ‘‘neoplasia’’ is more accu-
rate than the earlier terms ‘‘adenomas’’ and ‘‘adenomatosis’’
for MEN syndromes that include a malignant component.
Second, the recognized MEN syndromes are familial
disorders with autosomal dominant inheritance. Therefore,
they are appropriately called ‘‘familial multiple endocrine
syndromes.’’ Nonfamilial MEN combinations should be
considered separately.
Third, definition of a new MEN syndrome should be
based on a unique and primary endocrine cell pattern. In this
connection, the thyroid gland (follicular cells and C cells) and
the adrenal gland (cortex and medulla) each have two distinct
cell populations and thus have the possibility of contributing
one or both cell types to a new syndrome. Carcinoid tumor
may present a problem: the tumor has various cell types,
multiple sites of origin (gut, lung, thymus, etc), multiple
hormone products, some of which may be site-related,83 and
may be primary (as when a component of MEN 169) or
secondary (as when associated with type 2 chronic atrophic
gastritis11). Pheochromocytoma (adrenal paraganglioma) and
extra-adrenal paraganglioma, which are closely related tumors,
Authors’ Suggested
Designation Reference
Carney et al12
MEN 3a Griffiths et al37,38 Wheeler et al83
MEN 3b Griffiths et al37,38 Wheeler et al83
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Am J Surg Pathol  Volume 29, Number 2, February 2005
might tentatively be classified tentatively as the same tumor.
Probable precursors of certain neoplasms (thyroid C-cell
hyperplasia and adrenal medullary hyperplasia) also should
probably be considered equivalent to the definitive tumors. A
newly identified familial combination of endocrine cell tumors
would merit the next available Arabic numeral, following the
numeric terminology of Steiner et al.70
Fourth, familial MEN syndromes occur with and with-
out associated nonendocrine conditions. Following the alpha-
betic terminology of Sizemore et al,67 the uppercase letter ‘‘A’’
should be used to identify syndromes featuring only endocrine
tumors (or with a minimal nonendocrine component) and the
uppercase letter ‘‘B’’ should be reserved for MEN syndromes
having a major or dominant nonendocrine component.
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