2977Pheochromocytoma CHAPTER 387

false-positive results and then to repeat testing or perform a clonidine

suppression test (i.e., the measurement of plasma normetanephrine 3 h

after oral administration of 300 μg of clonidine). Other pharmacologic

tests, such as the phentolamine test and the glucagon provocation test,

are of relatively low sensitivity and are not recommended.

Diagnostic Imaging A variety of methods have been used to

localize pheochromocytomas and paragangliomas (Table 387-2,

Figs. 387-2, 387-3, and 387-4). CT and MRI are similar in sensitivity

and should be performed with contrast. T2-weighted MRI with gadolinium contrast is optimal for detecting pheochromocytomas and is

somewhat better than CT for imaging extra-adrenal pheochromocytomas and paragangliomas. About 5% of adrenal incidentalomas, which

usually are detected by CT or MRI, prove to be pheochromocytomas

upon endocrinologic evaluation, but the presence of pheochromocytomas is unlikely if unenhanced CT reveals an attenuation of <10 HU.

Tumors also can be localized by procedures using radioactive tracers,

including 131I- or 123I-metaiodobenzylguanidine (MIBG) scintigraphy, 111In-somatostatin analogue scintigraphy, 18F-DOPA positron emission

tomography (PET), 68Ga-DOTATATE PET, or 18F-fluorodeoxyglucose

Jugular v.

Vagus n. Tympanic n.

Jugular p.

Intravagal p.

Intercarotid p.

Sup. laryngeal p.

Inf. laryngeal p.

Subclavian p.

Pulmonary p.

Descending aorta

Glossopharyngeal n.

Jugular

ganglion

Nodose

ganglion

Sup.

laryngeal a.

Int.

laryngeal a.

Recurrent

laryngeal n.

Aorticopulmonary p.

Coronary p.

A Adrenal

pheochromocytoma

B Extra-adrenal

pheochromocytoma

C Head and neck paraganglioma

FIGURE 387-1 The paraganglial system and topographic sites (in red) of pheochromocytomas and paragangliomas. (Figures A, B reproduced with permission from WM

Manger, RW Gifford: Clinical and experimental pheochromocytoma. Cambridge: Blackwell Science; 1996.)

plasma and urinary levels of catecholamines and metanephrines form

the cornerstone of diagnosis. The characteristic fluctuations in the

hormonal activity of tumors result in considerable variation in serial

catecholamine measurements. However, most tumors continuously

leak O-methylated metabolites, which are detected by measurement of

metanephrines.

Catecholamines and metanephrines can be measured by different methods, including high-performance liquid chromatography,

enzyme-linked immunosorbent assay, and liquid chromatography/

mass spectrometry. When pheochromocytoma is suspected on clinical

grounds (i.e., when values are three times the upper limit of normal),

this diagnosis is highly likely regardless of the assay used. However, as summarized in Table 387-2, the sensitivity and specificity

of available biochemical tests vary greatly, and these differences are

important in assessing patients with borderline elevations of different

compounds. Urinary tests for metanephrines (total or fractionated)

and catecholamines are widely available and are used commonly for

initial evaluation. Among these tests, those for the fractionated metanephrines and catecholamines are the most sensitive. Plasma tests are

more convenient and include measurements of catecholamines and

metanephrines. Measurements of plasma metanephrine are the most

sensitive and are less susceptible to false-positive elevations from stress,

including venipuncture. Although the incidence of false-positive test

results has been reduced by the introduction of newer assays, physiologic stress responses and medications that increase catecholamine

levels still can confound testing. Because the tumors are relatively rare,

borderline elevations are likely to represent false-positive results. In

this circumstance, it is important to exclude dietary or drug-related

factors (withdrawal of levodopa or use of sympathomimetics, diuretics,

tricyclic antidepressants, alpha and beta blockers) that might cause

TABLE 387-1 Clinical Features Associated with Pheochromocytoma,

Listed by Frequency of Occurrence

1. Headaches

2. Profuse sweating

3. Palpitations and tachycardia

4. Hypertension, sustained or

paroxysmal

5. Anxiety and panic attacks

6. Pallor

7. Nausea

8. Abdominal pain

9. Weakness

10. Weight loss

11. Paradoxical response to

antihypertensive drugs

12. Polyuria and polydipsia

13. Constipation

14. Orthostatic hypotension

15. Dilated cardiomyopathy

16. Erythrocytosis

17. Elevated blood sugar

18. Hypercalcemia

TABLE 387-2 Biochemical and Imaging Methods Used for Diagnosis of

Pheochromocytoma and Paraganglioma

DIAGNOSTIC METHOD SENSITIVITY SPECIFICITY

24-h urinary tests

Catecholamines +++ +++

 Fractionated metanephrines ++++ ++

Total metanephrines +++ ++++

Plasma tests

Catecholamines +++ ++

Free metanephrines ++++ +++

Imaging

CT ++++ +++

MRI ++++ +++

MIBG scintigraphy ++ ++++

Somatostatin receptor scintigraphya ++ ++

18Fluoro-DOPA PET/CT ++++ ++++

68Gallium-DOTATOC or DOTATATE PET/CT ++++ ++++

a

Values are particularly high in head and neck paragangliomas.

Abbreviations: MIBG, metaiodobenzylguanidine; PET/CT, positron emission

tomography plus CT. For the biochemical tests, the ratings correspond globally to

sensitivity and specificity rates as follows: ++, <85%; +++, 85–95%; and ++++, >95%.

2978 PART 12 Endocrinology and Metabolism

A B

FIGURE 387-2 Typical pheochromocytoma (adrenal unilateral). A. MRI. B. 18F-DOPA positron emission

tomography (PET). Tumor marked by arrows. (Part A was provided courtesy of Dr. Tobias Krauss, Freiburg.

Part B was provided courtesy of Dr. Juri Ruf, Freiburg.)

A

C D

B

FIGURE 387-3 Paragangliomas (extra-adrenal pheochromocytomas). A. Carotid body tumor. B. Thoracic tumor. C. Paraaortal tumor. D. Pelvic tumor at the anterior wall of

the urinary bladder. Tumors marked by arrows. (Part A was provided courtesy of Dr. Carsten Boedeker, Stralsund. Parts B and D were provided courtesy of Dr Tobias Krauss,

Freiburg. Part C was provided courtesy of Dr Martin Walz, Essen.)

(FDG) PET (Fig. 387-2B and 387-4A and B). For PET-CT with both 68Ga-DOTATATE and 18F-DOPA, the sensitivity and specificity are

very high (>95%). These agents are particularly useful in the documentation of hereditary syndromes but also in metastatic pheochromocytoma, because uptake is exhibited also in paragangliomas and

metastases.

Pathology Pheochromocytomas and paragangliomas are found at

the classical sites of the adrenal medulla (Fig. 387-2) and paraganglia

(Fig. 387-3). Histologically, the tumors often show a characteristic

“Zellballen” pattern, consisting of nests of neuroendocrine chief cells

with peripheral glial-like sustentacular cells. However, a broad spectrum of architectural and cytologic features can be seen. Immunohistochemistry

is positive for chromogranin and synaptophysin

in the chief cells and S-100 in the sustentacular cells (Fig. 387-5A-D). Increasingly, staining

with antibodies against the proteins encoded by

susceptibility genes for hereditary pheochromocytomas, such as SDHB, is used to histologically

demonstrate defects of these proteins, thereby

making germline mutations more likely (Fig.

387-5E and F).

Differential Diagnosis When the possibility

of a pheochromocytoma is being entertained,

other disorders to consider include essential

hypertension, anxiety attacks, use of cocaine or

amphetamines, mastocytosis or carcinoid syndrome (usually without hypertension), intracranial

lesions, clonidine withdrawal, autonomic epilepsy,

and factitious crises (usually from use of sympathomimetic amines). When an asymptomatic adrenal mass is identified, likely diagnoses other than

pheochromocytoma include a nonfunctioning

adrenal adenoma, an aldosteronoma, and a cortisol-producing adenoma (Cushing’s syndrome).

TREATMENT

Pheochromocytoma

Complete tumor removal, the ultimate therapeutic goal, can be

achieved by partial or total adrenalectomy. It is important to

preserve the normal adrenal cortex in order to prevent Addison’s

disease, particularly in hereditary disorders in which bilateral

pheochromocytomas are most likely. Preoperative preparation of

the patient has to be considered, and blood pressure should be

consistently <160/90 mmHg. Classically, blood pressure has been

2979Pheochromocytoma CHAPTER 387

FIGURE 387-4 Multiple and metastatic pheochromocytoma. A. Paraganglioma syndrome. A patient with the SDHD W5X mutation and PGL1 68Ga-DOTATATE positron

emission tomography (PET) demonstrating tumor uptake in the right jugular glomus, the right and left carotid body, both adrenal glands, and an interaortocaval paraganglion

(arrows). Note the physiologic accumulation of the radiopharmaceutical agent in the kidneys and the liver. B. 18F-DOPA PET of a patient with metastatic pheochromocytoma.

Several metastases marked by arrows. (Parts A and B were provided courtesy of Dr. Juri Ruf, Freiburg.)

A B

controlled by α-adrenergic blockers (oral phenoxybenzamine,

0.5–4 mg/kg of body weight). Because patients are volumeconstricted, liberal salt intake and hydration are necessary to avoid

severe orthostasis. Oral prazosin or intravenous phentolamine can

be used to manage paroxysms while adequate alpha blockade is

awaited. Beta blockers (e.g., 10 mg of propranolol three or four

times per day) can then be added. Other antihypertensives, such as

calcium channel blockers or angiotensin-converting enzyme inhibitors, have also been used effectively.

Surgery should be performed by teams of surgeons and anesthesiologists with experience in the management of pheochromocytomas. Blood pressure can be labile during surgery, particularly at the

outset of intubation or when the tumor is manipulated. Nitroprusside infusion is useful for intraoperative hypertensive crises, and

hypotension usually responds to volume infusion. The latter side

effect can, however, be avoided in normotensive pheochromocytoma patients by having only standby intraoperative nitroprusside,

which has been shown to be safe and avoids postoperative hypotension often caused by alpha blockers; the long-lasting guideline for

obligatory preoperative treatment with alpha blockers is under

discussion.

Minimally invasive techniques (laparoscopy or retroperitoneoscopy) have become the standard approaches in pheochromocytoma

surgery. They are associated with fewer complications, a faster

recovery, and optimal cosmetic results. Extra-adrenal abdominal

and most thoracic pheochromocytomas can also be removed endoscopically. Postoperatively, catecholamine normalization should be

documented. An adrenocorticotropic hormone (ACTH) test should

be used to exclude cortisol deficiency when bilateral adrenal cortex–

sparing surgery has been performed.

Head and neck paragangliomas are a challenge for surgeons,

since damage of adjacent tissue, mainly vessels or cranial nerves,

is a frequent permanent side effect. Careful consideration of best

management is important, and radiotherapy may be an alternative,

especially for large head and neck paragangliomas.

■ METASTATIC PHEOCHROMOCYTOMA

About 5–10% of pheochromocytomas and paragangliomas are metastatic. The diagnosis of malignant pheochromocytoma is problematic.

The typical histologic criteria of cellular atypia, presence of mitoses,

and invasion of vessels or adjacent tissues are insufficient for the diagnosis of malignancy in pheochromocytoma. Thus, the term malignant

pheochromocytoma has been replaced by metastatic pheochromocytoma

as suggested by the WHO and is restricted to tumors with lymph node

or distant metastases, the latter most commonly found by nuclear

medicine imaging in lungs, bone, or liver locations suggesting a vascular pathway of spread (Fig. 387-4B). Because hereditary syndromes

are associated with multifocal tumor sites, these features should be

anticipated in patients with germline mutations, especially of RET,

VHL, SDHD, or SDHB. However, distant metastases also occur in these

syndromes, especially in carriers of SDHB mutations.

Treatment of metastatic pheochromocytoma or paraganglioma is

challenging. Options include tumor mass reduction, alpha blockers for

symptoms, chemotherapy, nuclear medicine radiotherapy, and stereotactic radiation. The first-line choice is nuclear medicine therapy for

scintigraphically documented metastases, preferably with 131I-MIBG in

100–300 mCi doses over 3–6 cycles. Other options for radionuclide treatment are somatostatin receptor ligands, e.g., DOTATOC labeled with

yttrium-90 or lutetium-177, both for palliative outcomes. Averbuch’s chemotherapy protocol includes dacarbazine (600 mg/m2

 on days 1 and 2),

cyclophosphamide (750 mg/m2

 on day 1), and vincristine (1.4 mg/m2

on day 1), all repeated every 21 days for 3–6 cycles. Palliation (stable

disease to shrinkage) is achieved in about one-half of patients. Due to

increasing insights in the genetics of pheochromocytoma and their

molecular pathways, new targeted chemotherapeutic options such as

2980 PART 12 Endocrinology and Metabolism

sunitinib and temozolomide/thalidomide are under development. The

prognosis of metastatic pheochromocytoma or paraganglioma is variable, with 5-year survival rates of 30–60%.

■ PHEOCHROMOCYTOMA IN PREGNANCY

Pheochromocytomas occasionally are diagnosed in pregnancy and

can be very challenging to manage. Endoscopic removal, preferably in

the fourth to sixth month of gestation, is possible and can be followed

by uneventful childbirth. Regular screening in families with inherited

pheochromocytomas provides an opportunity to identify and remove

such tumors in women of reproductive age.

■ PHEOCHROMOCYTOMA-ASSOCIATED

SYNDROMES

About 25–33% of patients with a pheochromocytoma or paraganglioma have an inherited syndrome. At diagnosis, patients with inherited syndromes are a mean of ~15 years younger than patients with

sporadic tumors.

The best-known pheochromocytoma-associated syndrome is the

autosomal dominant disorder MEN 2 (Chap. 388). Both types of

MEN 2 (2A and 2B) are caused by mutations in RET, which encodes

a tyrosine kinase. The locations of RET mutations correlate with the

severity of disease and the type of MEN 2 (Chap. 388). MEN 2A is

characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism; MEN 2B also includes MTC and

pheochromocytoma as well as multiple mucosal neuromas, marfanoid

habitus, and other developmental disorders, although it typically lacks

hyperparathyroidism. MTC is found in virtually all patients with MEN

2, but pheochromocytoma occurs in only ~50% of these patients.

Nearly all pheochromocytomas in MEN 2 are benign and located in the

adrenals, often bilaterally. Pheochromocytoma may be symptomatic

before MTC. Prophylactic thyroidectomy is being performed in many

carriers of RET mutations; pheochromocytomas should be excluded

before any surgery in these patients.

VHL is an autosomal dominant disorder that predisposes to retinal

and cerebellar hemangioblastomas, which also occur in the brainstem and spinal cord (Fig. 387-6). Other important features of VHL

are clear cell renal carcinomas, pancreatic neuroendocrine tumors,

endolymphatic sac tumors of the inner ear, cystadenomas of the epididymis and broad ligament, and multiple pancreatic or renal cysts.

Although the VHL gene can be inactivated by all types of mutations,

patients with pheochromocytoma predominantly have missense mutations. About 20–30% of patients with VHL have pheochromocytomas,

but in some families, the incidence can reach 90%. The recognition of

pheochromocytoma as a VHL-associated feature provides an opportunity to diagnose retinal, central nervous system, renal, and pancreatic

tumors at a stage when effective treatment may still be possible.

NF1 was the first described pheochromocytoma-associated syndrome. The NF1 gene functions as a tumor suppressor by regulating

the Ras signaling cascade. Classic features of neurofibromatosis include

multiple neurofibromas, café au lait spots, axillary freckling of the skin,

and Lisch nodules of the iris. Pheochromocytomas occur in only ~1%

of these patients and are located predominantly in the adrenals. Metastatic pheochromocytoma is not uncommon in NF1.

The paraganglioma syndromes (PGLs) have been classified by genetic

analyses of families with head and neck paragangliomas. The susceptibility genes encode subunits of the enzyme SDH, a component in the

Krebs cycle and the mitochondrial electron transport chain. SDH is

formed by four subunits (A–D). Mutations of SDHA (PGL5), SDHB

(PGL4), SDHC (PGL3), SDHD (PGL1), and SDHAF2 (PGL2) predispose to the PGLs. The transmission of the disease in carriers of SDHA,

SDHB, and SDHC germline mutations is autosomal dominant. In

contrast, in virtually all SDHD and SDHAF2 families, only the progeny

of affected fathers develop tumors if they inherit the mutation. PGL1

is most common, followed by PGL4; PGL2, PGL3, and PGL5 are rare.

Adrenal, extra-adrenal abdominal, and thoracic pheochromocytomas,

which are components of PGL1, PGL4, and PGL5, are rare in PGL3 and

absent in PGL2 (Fig. 387-4A). About one-third of patients with PGL4

develop metastases, which is the highest rate in pheochromocytomaassociated syndromes. Other syndromes with metastatic pheochromocytomas are mainly VHL, NF1, and PGL1.

Other familial pheochromocytoma has been attributed to hereditary, mainly adrenal tumors in patients with germline mutations in the

genes TMEM127 and MAX. Transmission is also autosomal dominant,

and mutations of MAX, like those of SDHD, cause tumors only if inherited from the father.

A B C

D E F

FIGURE 387-5 Histology and immunohistochemistry of pheochromocytoma. A. Hematoxylin and eosin, B. chromogranin, C. synaptophysin, C and B stain chief cells; D.

S-100 stains sustentacular cells. E, F. Immunohistochemistry with SDHB antibody: positive staining (granular cytoplasmic staining) indicates intact SDHB (E), whereas

negative staining (endothelial cells positive as internal control) (F) indicates structurally changed or absent SDHB due to a germline mutation in the SDHB gene, which was

confirmed by molecular genetic analysis of a blood sample. (Parts A–D and F were used with permission from Dr Helena Leijon, Helsinki. Part E was provided courtesy of

Dr. Kurt Werner Schmid, Essen.)

2981Pheochromocytoma CHAPTER 387

A

C

E G H

D F

B

FIGURE 387-6 von Hippel–Lindau disease. Tumors and cysts marked by arrows. A. Retinal angioma (arrows with a pair of feeding vessels). All subsequent panels show

findings on MRI. B–D. Hemangioblastomas of the cerebellum (large cyst and a solid mural tumor) (B) in brainstem (in part cystic) (C) and spinal cord (thoracic) (D).

E. Bilateral renal clear cell carcinomas with two tumors on each side F. Multiple pancreatic cysts. G. Microcystic serous pancreatic cystadenoma (with multiple tiny

spaces). H. Two pancreatic islet cell tumors. (Part A was provided courtesy of Dr. Dieter Schmidt. Part B was provided courtesy of Dr. Christian Taschner, Freiburg. Part C

was provided courtesy of Dr. Sven Glaesker, Brussels. Part D was used with permission from Dr. Jan-Helge Klingler, Freiburg. Part E was provided courtesy of Dr. Cordula

Jilg, Freiburg. Parts F–H were provided courtesy of Dr Tobias Krauss, Freiburg.)

■ GENETIC SCREENING OF PATIENTS WITH

PHEOCHROMOCYTOMA OR PARAGANGLIOMA

Effective preventive medicine for pheochromocytoma and pheochromocytoma-associated diseases requires management according

to identified germline mutations in susceptibility genes. In addition

to family history, general features suggesting an inherited syndrome

include young age, multifocal tumors, extra-adrenal tumors, and metastatic tumors (Table 387-3 and Fig. 387-7). Because of the relatively

high prevalence of familial syndromes among patients who present

with pheochromocytoma or paraganglioma, it is useful to identify

germline mutations even in patients without a known family history.

A first step is to search for clinical features of inherited syndromes and

TABLE 387-3 Patterns of Occurrence in Inherited Pheochromocytoma and Paraganglioma–Associated Syndromes

MUTATED GENE

ADRENAL

TUMORS

HEAD AND

NECK TUMORS

EXTRA-ADRENAL

RETROPERITONEAL OR

PELVIC TUMORS

THORACIC

TUMORS

MULTIPLE

TUMORS

BILATERAL

ADRENAL

TUMORS

METASTATIC

TUMORS

FAMILY HISTORY

IN PROBANDS FOR

COMPONENTS OF THE

GIVEN SYNDROME

MAX +++++ <x + <x +++++ ++++ ++ +++

NF1 +++++ <+ + <+ + ++ + ++

RET +++++ <+ <+ <+ ++++ ++++ <+ +

SDHA ++ ++++ ++ + + <+ + +

SDHB ++++ +++ +++ + ++ <+ +++ ++

SDHC <+ +++++ <+ + + <+ <+ ++

SDHD ++ +++++ + + ++++ <+ + +++

VHL +++++ <+ + + ++++ +++ + ++++

TMEM127 +++++ + + + ++ ++ <+ +

Note: Frequencies in percentage (<+: 0–4%; +: 5–19%; ++: 20–39%; +++: 40–59%; ++++: 60–79%; +++++: 80–100%) of clinical characteristics of pheochromocytomas/

paragangliomas of patients with germline mutations of the genes MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, VHL, and TMEM127; for other genes, the data are too limited

to include in this summary.

2982 PART 12 Endocrinology and Metabolism

FIGURE 387-7 Mutation distribution in the VHL, RET, SDHB, SDHC, SDHD, and NF1 genes in 4156 patients with pheochromocytomas and paragangliomas from the EuropeanAmerican Pheochromocytoma-Paraganglioma Registry based in Freiburg, Germany, Padova, Italy, and Rochester, Minnesota, and updated as of December 20, 2020.

A. Correlation with age. The bars depict the frequency of sporadic (spor) or various inherited forms of pheochromocytoma in different age groups. The inherited disorders

are much more common among younger individuals presenting with pheochromocytoma. B. Percentages of mutated genes in hereditary pheochromocytomas and

paragangliomas. C–G. Germline mutations according to multiple (C), metastatic (D), hereditary (E), extra-adrenal retroperitoneal (F), head and neck paragangliomas (HNP)

(G), and thoracic (H). (Data from the Freiburg International Pheochromocytoma and Paraganglioma Registry, 2017. Figures courtesy of Dr. Charis Eng, Cleveland; Dr. Irina

Bancos, Rochester; Dr. Birke Bausch, Freiburg; Dr. Giuseppe Opocher and Dr. Francesca Schiavi, Padova.)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Decade 1 Decade 2 Decade 3 Decade 4 Decade 5 Decade 6 Decade 7-9

Percentages of Germline Mutations in

Pheochromocytoma Susceptibility Genes

VHL SDHA SDHB SDHC SDHD MAX TMEM127 NF1 RET Spor

Multiple Metastatic Positive Family

History

Extraadrenal HNP Thoracic

to obtain an in-depth, multigenerational family history. Each of these

syndromes exhibits autosomal dominant transmission with variable

penetrance, but a proband with a mother affected by paraganglial

tumors is not predisposed to PLG1 and PGL2 (SDHD and SDHAF2

mutation carrier). Cutaneous neurofibromas, café au lait spots, and

axillary freckling suggest neurofibromatosis. Germline mutations

in NF1 have nearly never been reported in patients with sporadic

pheochromocytomas. Thus, NF1 testing is not needed in the absence

of other clinical features of neurofibromatosis. A personal or family

history of MTC or an elevation of serum calcitonin strongly suggests

MEN 2 and should prompt testing for RET mutations. A history of

visual impairment or tumors of the cerebellum, brain stem, spinal

2983 Multiple Endocrine Neoplasia Syndromes CHAPTER 388

cord or the kidney suggests the possibility of VHL. A personal and/

or family history of head and neck paraganglioma suggests PGL1 or

PGL4.

A single adrenal pheochromocytoma in a patient with an otherwise

unremarkable history may still be associated with mutations of VHL,

RET, SDHB, or SDHD (in decreasing order of frequency). Two-thirds

of extra-adrenal tumors are associated with one of these syndromes,

and multifocal tumors occur with decreasing frequency in carriers of

RET, SDHD, VHL, SDHB, and MAX mutations. About 30% of head and

neck paragangliomas are associated with germline mutations of one of

the SDH subunit genes (most often SDHD) and are rare in carriers of

VHL, RET, MAX, and TMEM127 mutations. Immunohistochemistry is

helpful in the preselection of hereditary pheochromocytoma. Negative

immunostaining with antibodies to SDHB (Fig. 387-5F), TMEM127,

and MAX may predict mutations of the SDHx (PGL1-5), TMEM127,

and MAX genes, respectively.

Whole genome sequence analysis is increasingly replacing targeted

Sanger sequencing. It is now possible to search for germline mutations in

a set of genes, such that all susceptibility genes for pheochromocytomaassociated syndromes could be analyzed in one procedure. Of note,

sequencing protocols may not detect large deletions of one or more exons.

Once the underlying syndrome is diagnosed, the benefit of genetic

testing can be extended to relatives. For this purpose, it is necessary

to identify the germline mutation in the proband and, after genetic

counseling, to perform DNA sequence analyses of the responsible gene

in relatives to determine whether they are affected. Other family members may benefit when individuals who carry a germline mutation are

biochemically screened for paraganglial tumors.

Asymptomatic paraganglial tumors, now often detected in patients

with hereditary tumors and their relatives, are challenging to manage.

Watchful waiting strategies have been introduced. Head and neck

paragangliomas—mainly carotid body, jugular, and vagal tumors—are

increasingly treated by radiation, since surgery is frequently associated

with permanent palsy of cranial nerves II, VII, IX, X, XI, and XII. Nevertheless, tympanic paragangliomas are symptomatic early, and most of

these tumors can easily be resected, with subsequent improvement of

hearing and alleviation of tinnitus.

■ FURTHER READING

Bancos I et al: Maternal and fetal outcomes in pheochromocytoma

and pregnancy: A multi-center retrospective cohort study and systematic review of literature. Lancet Diabetes Endocrinol 9:13, 2021.

Berends AMA et al: Incidence of pheochromocytoma and sympathetic paraganglioma in the Netherlands: A nationwide study and

systematic review. Eur Intern Med 51:68, 2018.

Canu L et al: CT characteristics of pheochromocytoma: Relevance for

the evaluation of adrenal incidentaloma. J Clin Endocrinol Metab

104:312, 2019.

Groeben H et al: International multicentre review of perioperative

management and outcome for catecholamine-producing tumours. Br

J Surg 107:e170, 2020.

Hamidi O et al: Malignant pheochromocytoma and paraganglioma:

272 patients over 55 years. J Clin Endocrinol Metab 10:3296, 2017.

Lenders JW et al: Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: A position statement and consensus of the Working Group on Endocrine

Hypertension of the European Society of Hypertension. J Hypertens

38:1443, 2020.

Neumann HPH et al: Comparison of pheochromocytoma-specific

morbidity and mortality among adults with bilateral pheochromocytomas undergoing total adrenalectomy vs cortical-sparing adrenalectomy. JAMA Netw Open 2:e198898, 2019.

Taïeb D et al: European Association of Nuclear Medicine Practice

Guideline/Society of Nuclear Medicine and Molecular Imaging

Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 46:2112,

2019.

Multiple endocrine neoplasia (MEN) is characterized by a predilection

for tumors involving two or more endocrine glands. Four major forms

of MEN are recognized and referred to as MEN types 1–4 (MEN 1–4)

(Table 388-1). Each type of MEN is inherited as an autosomal dominant syndrome or may occur sporadically, that is, without a family history. However, this distinction between familial and sporadic forms is

often difficult because family members with the disease may have died

before symptoms developed. In addition to MEN 1–4, at least six other

syndromes are associated with multiple endocrine and other organ

neoplasias (MEONs) (Table 388-2). These MEONs include the hyperparathyroidism-jaw tumor (HPT-JT) syndrome, Carney complex, von

Hippel–Lindau disease (Chap. 387), neurofibromatosis type 1 (Chap.

90), Cowden’s syndrome (CWS), and McCune-Albright syndrome

(MAS) (Chap. 412); all of these are inherited as autosomal dominant

disorders, except for MAS, which is caused by mosaic expression of a

postzygotic somatic cell mutation (Table 388-2).

A diagnosis of a MEN or MEON syndrome may be established in an

individual by one of three criteria: (1) clinical features (two or more of

the associated tumors [or lesions] in an individual); (2) familial pattern

(one of the associated tumors [or lesions] in a first-degree relative of

a patient with a clinical diagnosis of the syndrome); and (3) genetic

analysis (a germline mutation in the associated gene in an individual,

who may be clinically affected or asymptomatic). Mutational analysis

in MEN and MEON syndromes is helpful in clinical practice to (1)

confirm the clinical diagnosis; (2) identify family members who harbor the mutation and require screening for relevant tumor detection

and early/appropriate treatment; and (3) identify the ~50% of family

members who do not harbor the germline mutation and can, therefore,

be alleviated of the anxiety of developing associated tumors. This latter

aspect also helps to reduce health care costs by reducing the need for

unnecessary biochemical and radiologic investigations.

■ MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

Clinical Manifestations MEN type 1 (MEN 1), which is also

referred to as Wermer’s syndrome, is characterized by the triad of

tumors involving the parathyroids, pancreatic islets, and anterior pituitary. In addition, adrenal cortical tumors, carcinoid tumors usually

of the foregut, meningiomas, facial angiofibromas, collagenomas, and

lipomas may also occur in some patients with MEN 1. Combinations

of the affected glands and their pathologic features (e.g., hyperplastic

adenomas of the parathyroid glands) may differ in members of the

same family and even between identical twins. In addition, a nonfamilial (e.g., sporadic) form occurs in 8–14% of patients with MEN 1,

and molecular genetic studies have confirmed the occurrence of de

novo mutations of the MEN1 gene in ~10% of patients with MEN 1.

The prevalence of MEN 1 is ~0.25% based on randomly chosen postmortem studies but is 1–18% among patients with primary hyperparathyroidism, 16–38% among patients with pancreatic islet tumors, and

<3% among patients with pituitary tumors. The disorder affects all

age groups, with a reported age range of 5–81 years, with clinical and

biochemical manifestations developing in the vast majority by the fifth

decade. The clinical manifestations of MEN 1 are related to the sites

of tumors and their hormonal products. In the absence of treatment,

endocrine tumors are associated with an earlier mortality in patients

with MEN 1, with a 50% probability of death by the age of 50 years.

The cause of death is usually a malignant tumor, often from a pancreatic neuroendocrine tumor (NET) or foregut carcinoid. In addition,

the treatment outcomes of patients with MEN 1–associated tumors are

not as successful as those in patients with non–MEN 1 tumors. This

is because MEN 1–associated tumors, with the exception of pituitary

388 Multiple Endocrine

Neoplasia Syndromes

R. V. Thakker

2984 PART 12 Endocrinology and Metabolism

TABLE 388-1 Multiple Endocrine Neoplasia (MEN) Syndromes

TYPE (CHROMOSOMAL

LOCATION)

TUMORS (ESTIMATED

PENETRANCE)

GENE AND MOST

FREQUENTLY

MUTATED CODONS

MEN 1 (11q13) Parathyroid adenoma (90%)

Enteropancreatic tumor

(30–70%)

• Gastrinoma (>50%)

• Insulinoma (10–30%)

• Nonfunctioning and PPoma

(20–55%)

• Glucagonoma (<3%)

• VIPoma (<1%)

Pituitary adenoma (15–50%)

• Prolactinoma (60%)

• Somatotrophinoma (25%)

• Corticotrophinoma (<5%)

• Nonfunctioning (<5%)

Associated tumors

• Adrenal cortical tumor

(20–70%)

• Pheochromocytoma (<1%)

• Bronchopulmonary NET (2%)

• Thymic NET (2%)

• Gastric NET (10%)

• Lipomas (>33%)

• Angiofibromas (85%)

• Collagenomas (70%)

• Meningiomas (8%)

MEN1

83/84, 4-bp del (≈4%)

119, 3-bp del (≈3%)

209-211, 4-bp del

(≈8%)

418, 3-bp del (≈4%)

514-516, del or ins

(≈7%)

Intron 4 ss (≈10%)

MEN 2 (10 cen-10q11.2)

MEN 2A MTC (90%) RET

Pheochromocytoma (>50%)

Parathyroid adenoma (10–25%)

634, e.g., Cys → Arg

(~85%)

MTC only MTC (100%) RET 618, missense

(>50%)

 MEN 2B (also known

as MEN 3)

MTC (>90%)

Pheochromocytoma (>50%)

Associated abnormalities

(40–50%)

• Mucosal neuromas

• Marfanoid habitus

• Medullated corneal nerve

fibers

• Megacolon

RET 918, Met → Thr

(>95%)

MEN 4 (12p13) Parathyroid adenomaa

Pituitary adenomaa

Reproductive organ tumorsa

(e.g., testicular cancer,

neuroendocrine cervical

carcinoma)

?Adrenal + renal tumorsa

CDKN1B; no

common mutations

identified to date

a

Insufficient numbers reported to provide prevalence information.

Note: Autosomal dominant inheritance of the MEN syndromes has been

established.

Abbreviations: del, deletion; ins, insertion; MTC, medullary thyroid cancer; NET,

neuroendocrine tumor; PPoma, pancreatic polypeptide–secreting tumor; VIPoma,

vasoactive intestinal polypeptide–secreting tumor.

Source: Adapted with permission from RV Thakker: Multiple endocrine neoplasia—

syndromes of the twentieth century. J Clin Endocrinol Metab 83:2617, 1998.

NETs, are usually multiple, making it difficult to achieve a successful

surgical cure. Occult metastatic disease is also more prevalent in MEN

1, and the tumors may be larger, more aggressive, and resistant to

treatment.

Parathyroid Tumors (See also Chap. 410) Primary hyperparathyroidism occurs in ~90% of patients and is the most common

TABLE 388-2 Multiple Endocrine and Other Organ Neoplasia (MEON)

Syndromes

DISEASEa GENE PRODUCT

CHROMOSOMAL

LOCATION

Hyperparathyroidism-jaw

tumor (HPT-JT)

Parafibromin 1q31.2

Carney complex

CNC1 PRAKAR1A 17q24.2

CNC2 ?b 2p16

von Hippel–Lindau

disease (VHL)

pVHL (elongin) 3p25

Neurofibromatosis

type 1 (NF1)

Neurofibromin 17q11.2

Cowden’s syndrome

(CWS)

CWS1 PTEN 10q23.31

CWS2 SDHB 1p36.13

CWS3 SDHD 11q23.1

CWS4 KLLN 10q23.31

CWS5 PIK3CA 3q26.32

CWS6 AKT1 14q32.33

CWS7 SEC23B 20p11.23

McCune-Albright

syndrome (MAS)

Gs

α 20q13.32

a

The inheritance for these disorders is autosomal dominant, except MAS, which

is due to mosaicism that results from the postzygotic somatic cell mutation of the

GNAS1 gene, encoding Gs

α. b

?, unknown.

feature of MEN 1. Patients may have asymptomatic hypercalcemia or

vague symptoms associated with hypercalcemia (e.g., polyuria, polydipsia, constipation, malaise, or dyspepsia). Nephrolithiasis and osteitis

fibrosa cystica (less commonly) may also occur. Biochemical investigations reveal hypercalcemia, usually in association with elevated circulating parathyroid hormone (PTH) (Table 388-3). The hypercalcemia

is usually mild, and severe hypercalcemia or parathyroid cancer is a

rare occurrence. Additional differences in the primary hyperparathyroidism of patients with MEN 1, as opposed to those without MEN 1,

include an earlier age at onset (20–25 vs 55 years) and an equal maleto-female ratio (1:1 vs 1:3). Preoperative imaging (e.g., neck ultrasound

with 99mTc-sestamibi parathyroid scintigraphy) is of limited benefit

because all parathyroid glands may be affected, and neck exploration

may be required irrespective of preoperative localization studies.

TREATMENT

Parathyroid Tumors

Surgical removal of the abnormally overactive parathyroids in

patients with MEN 1 is the definitive treatment. However, it is controversial whether to perform subtotal (e.g., removal of 3.5 glands)

or total parathyroidectomy with or without autotransplantation

of parathyroid tissue in the forearm, and whether surgery should

be performed at an early or late stage. Minimally invasive parathyroidectomy is not recommended because all four parathyroid

glands are usually affected with multiple adenomas or hyperplasia.

Surgical experience should be taken into account given the variability in pathology in MEN 1. Calcimimetics (e.g., cinacalcet),

which act via the calcium-sensing receptor, have been used to treat

primary hyperparathyroidism in some patients when surgery is

unsuccessful or contraindicated.

Pancreatic Tumors (See also Chap. 84) The incidence of

pancreatic islet cell tumors, which are NETs, in patients with MEN 1

ranges from 30 to 80% in different series. Most of these tumors (Table

388-1) produce excessive amounts of hormone (e.g., gastrin, insulin,

glucagon, vasoactive intestinal polypeptide [VIP]) and are associated

with distinct clinical syndromes, although some are nonfunctioning or

2985 Multiple Endocrine Neoplasia Syndromes CHAPTER 388

nonsecretory. These pancreatic islet cell tumors have an earlier age at

onset in patients with MEN 1 than in patients without MEN 1.

Gastrinoma Gastrin-secreting tumors (gastrinomas) are associated with marked gastric acid production and recurrent peptic

ulcerations, a combination referred to as Zollinger-Ellison syndrome.

Gastrinomas occur more often in patients with MEN 1 who are aged

>30 years. Recurrent severe multiple peptic ulcers, which may perforate, and cachexia are major contributors to the high mortality. Patients

with Zollinger-Ellison syndrome may also suffer from diarrhea and

steatorrhea. The diagnosis is established by demonstration of an elevated fasting serum gastrin concentration in association with increased

basal gastric acid secretion (Table 388-3). However, the diagnosis of

Zollinger-Ellison syndrome may be difficult in hypercalcemic MEN

1 patients because hypercalcemia can also cause hypergastrinemia.

Ultrasonography, endoscopic ultrasonography, computed tomography

(CT), nuclear magnetic resonance imaging (MRI), selective abdominal

angiography, venous sampling, and somatostatin receptor scintigraphy

(SRS) are helpful in localizing the tumor prior to surgery. Gastrinomas

represent >50% of all pancreatic NETs in patients with MEN 1, and

~20% of patients with gastrinomas will be found to have MEN 1. Gastrinomas, which may also occur in the duodenal mucosa, are the major

cause of morbidity and mortality in patients with MEN 1.

TREATMENT

Gastrinoma

Medical treatment of patients with MEN 1 and Zollinger-Ellison syndrome is directed toward reducing basal acid output to <10 mmol/L.

Parietal cell H+-K+-adenosine triphosphatase (ATPase) inhibitors

(e.g., omeprazole or lansoprazole) reduce acid output and are the

drugs of choice for gastrinomas. Some patients may also require

additional treatment with the histamine H2

 receptor antagonists

cimetidine or ranitidine. The role of surgery in the treatment of

gastrinomas in patients with MEN 1 is controversial. The goal

of surgery is to reduce the risk of distant metastatic disease and

improve survival. For a nonmetastatic gastrinoma situated in the

pancreas, surgical excision is often effective. However, the risk of

hepatic metastases increases with tumor size, such that 25–40% of

patients with pancreatic NETs >4 cm develop hepatic metastases,

and 50–70% of patients with tumors 2–3 cm in size have lymph

node metastases. Survival in MEN 1 patients with gastrinomas

<2.5 cm in size is 100% at 15 years, but 52% at 15 years, if metastatic

disease is present. The presence of lymph node metastases does not

appear to adversely affect survival. Surgery for gastrinomas that

are >2–2.5 cm has been recommended, because the disease-related survival in these patients is improved following surgery. In

addition, duodenal gastrinomas, which occur more frequently in

patients with MEN 1, have been treated successfully with surgery.

However, in most patients with MEN 1, gastrinomas are multiple

or extrapancreatic, and with the exception of duodenal gastrinomas, surgery is rarely successful. For example, the results of one

study revealed that only ~15% of patients with MEN 1 were free

of disease immediately after surgery, and at 5 years, this number

had decreased to ~5%; the respective outcomes in patients without

MEN 1 were better, at 45 and 40%. Given these findings, most specialists recommend a nonsurgical management for gastrinomas in

MEN 1, except as noted earlier for smaller, isolated lesions. Treatment of disseminated gastrinomas is difficult. Chemotherapy with

streptozotocin and 5-fluorouracil; hormonal therapy with octreotide or lanreotide, which are human somatostatin analogues (SSAs);

selected internal radiation therapy (SIRT); radiofrequency ablation;

peptide radio receptor therapy (PRRT); hepatic artery embolization; administration of human leukocyte interferon; and removal of

all resectable tumor have been successful in some patients.

Insulinoma These β islet cell insulin-secreting tumors represent

10–30% of all pancreatic tumors in patients with MEN 1. Patients with

an insulinoma present with hypoglycemic symptoms (e.g., weakness,

headaches, sweating, faintness, seizures, altered behavior, weight gain)

that typically develop after fasting or exertion and improve after glucose

intake. The most reliable test is a supervised 72-h fast. Biochemical

investigations reveal increased plasma insulin concentrations in association with hypoglycemia (Table 388-3). Circulating concentrations of

C peptide and proinsulin, which are also increased, are useful in establishing the diagnosis. It also is important to demonstrate the absence

of sulfonylureas in plasma and urine samples obtained during the

investigation of hypoglycemia (Table 388-3). Surgical success is greatly

enhanced by preoperative localization by endoscopic ultrasonography, CT scanning, or celiac axis angiography. Additional localization

methods may include preoperative and perioperative percutaneous

transhepatic portal venous sampling, selective intraarterial stimulation

with hepatic venous sampling, and intraoperative direct pancreatic

ultrasonography. Insulinomas occur in association with gastrinomas in

10% of patients with MEN 1, and the two tumors may arise at different

times. Insulinomas occur more often in patients with MEN 1 who are

aged <40 years, and some arise in individuals aged <20 years. In contrast, in patients without MEN 1, insulinomas generally occur in those

aged >40 years. Insulinomas may be the first manifestation of MEN 1 in

10% of patients, and ~4% of patients with insulinomas will have MEN 1.

TREATMENT

Insulinoma

Medical treatment, which consists of frequent carbohydrate meals

and diazoxide or octreotide, is not always successful, and surgery

is the optimal treatment. Surgical treatment, which ranges from

enucleation of a single tumor to a distal pancreatectomy or partial

pancreatectomy, has been curative in many patients. Chemotherapy

TABLE 388-3 Biochemical and Radiologic Screening in Multiple Endocrine Neoplasia Type 1

TUMOR AGE TO BEGIN (YEARS) BIOCHEMICAL TEST (PLASMA OR SERUM) ANNUALLY IMAGING TEST (TIME INTERVAL)

Parathyroid 8 Calcium, PTH None

Pancreatic NETs

Gastrinoma 20 Gastrin (± gastric pH) None

Insulinoma 5 Fasting glucose, insulin None

Other pancreatic NET <10 Chromogranin A; pancreatic polypeptide, glucagon,

vasoactive intestinal peptide

MRI, CT, or EUS (annually)

Anterior pituitary 5 Prolactin, IGF-I MRI (every 3 years)

Adrenal <10 None unless symptoms or signs of functioning tumor and/or

tumor >1 cm identified on imaging

MRI or CT (annually with pancreatic imaging)

Thymic and bronchial

carcinoid

15 None CT or MRI (every 1–2 years)

Abbreviations: CT, computed tomography; EUS, endoscopic ultrasound; IGF-I, insulin-like growth factor I; MRI, magnetic resonance imaging; PTH, parathyroid hormone.

Source: Data from PJ Newey, RV Thakker: Role of multiple endocrine neoplasia type 1 mutational analysis in clinical practice. Endocr Pract 17, 2011 and RV Thakker:

Multiple endocrine neoplasia type 1 (MEN1). Translational Endocrinology and Metabolism, Vol 2. Chevy Chase, MD: The Endocrine Society; 2011.

2986 PART 12 Endocrinology and Metabolism

(streptozotocin, 5-fluorouracil, and doxorubicin), PRRT (e.g., with

177Lu-DOTATATE), or hepatic artery embolization has been used

for metastatic disease.

Glucagonoma These glucagon-secreting pancreatic NETs occur in

<3% of patients with MEN 1. The characteristic clinical manifestations

of a skin rash (necrolytic migratory erythema), weight loss, anemia,

and stomatitis may be absent. The tumor may have been detected in an

asymptomatic patient with MEN 1 undergoing pancreatic imaging or

by the finding of glucose intolerance and hyperglucagonemia.

TREATMENT

Glucagonoma

Surgical removal of the glucagonoma is the treatment of choice.

However, treatment may be difficult because ~50–80% of patients

have metastases at the time of diagnosis. Medical treatment with

SSAs (e.g., octreotide or lanreotide) or chemotherapy with streptozotocin and 5-fluorouracil has been successful in some patients, and

hepatic artery embolization has been used to treat metastatic disease.

Vasoactive Intestinal Peptide (VIP) Tumors (VIPomas)

VIPomas have been reported in only a few patients with MEN 1. This

clinical syndrome is characterized by watery diarrhea, hypokalemia,

and achlorhydria (WDHA syndrome), which is also referred to as the

Verner-Morrison syndrome, or the VIPoma syndrome. The diagnosis

is established by excluding laxative and diuretic abuse, confirming a

stool volume in excess of 0.5–1.0 L/d during a fast, and documenting a

markedly increased plasma VIP concentration.

TREATMENT

VIPomas

Surgical management of VIPomas, which are mostly located in

the tail of the pancreas, can be curative. However, in patients with

unresectable tumor, SSAs, such as octreotide and lanreotide, may

be effective. Streptozotocin with 5-fluorouracil may be beneficial, along with hepatic artery embolization for the treatment of

metastases.

Pancreatic Polypeptide-Secreting Tumors (PPomas) and

Nonfunctioning Pancreatic NETs PPomas are found in a large

number of patients with MEN 1. No pathologic sequelae of excessive

polypeptide (PP) secretion are apparent, and the clinical significance

of PP is unknown. Many PPomas may have been unrecognized or

classified as nonfunctioning pancreatic NETs, which likely represent

the most common enteropancreatic NET associated with MEN 1

(Fig. 388-1). The absence of both a clinical syndrome and specific

biochemical abnormalities may result in a delayed diagnosis of

nonfunctioning pancreatic NETs, which are associated with a worse

prognosis than other functioning tumors, including insulinoma and

gastrinoma. The optimum screening method and its timing interval for

nonfunctioning pancreatic NETs remain to be established. At present,

endoscopic ultrasound likely represents the most sensitive method of

detecting small pancreatic tumors, but SRS is the most reliable method

for detecting metastatic disease (Table 388-3).

TREATMENT

PPomas and Nonfunctioning Pancreatic NETs

The management of nonfunctioning pancreatic NETs in the asymptomatic patient is controversial. One recommendation is to undertake surgery irrespective of tumor size after biochemical assessment

is complete. Alternatively, other experts recommend surgery based

on tumor size, using either >1 cm or >2 cm at different centers. Pancreatoduodenal surgery is successful in removing the tumors in 80%

of patients, but >40% of patients develop complications, including

diabetes mellitus, frequent steatorrhea, early and late dumping syndromes, and other gastrointestinal symptoms. However, ~50–60% of

patients treated surgically survive >5 years. When considering these

recommendations, it is important to consider that occult metastatic

disease (e.g., tumors not detected by imaging investigations) is likely

to be present in a substantial proportion of these patients at the time

of presentation. Inhibitors of tyrosine kinase receptors (TKRs) and

of the mammalian target of rapamycin (mTOR) signaling pathway

have been reported to be effective in treating pancreatic NET metastases and in doubling the progression-free survival time. Additional

treatments for metastatic disease include PRRT using 177Lu-DOTATATE, chemotherapy, radiofrequency ablation, transarterial chemoemobilization, and SIRT.

FIGURE 388-1 Pancreatic nonfunctioning neuroendocrine tumor (NET) in a

14-year-old patient with multiple endocrine neoplasia type 1 (MEN 1). A. An

abdominal magnetic resonance imaging scan revealed a low-intensity >2.0 cm

(anteroposterior maximal diameter) tumor within the neck of pancreas. There

was no evidence of invasion of adjacent structures or metastases. The tumor

is indicated by white dashed circle. B. The pancreatic NET was removed by

surgery, and macroscopic examination confirmed the location of the tumor

(white dashed circles) in the neck of the pancreas. Immunohistochemistry

showed the tumor to immunostain for chromogranin A, but not gastrointestinal

peptides or menin, thereby confirming that it was a nonsecreting NET due to loss

of menin expression. (Part A reproduced with permission from PJ Newey et al:

Asymptomatic children with multiple endocrine neoplasia type 1 mutations may

harbor nonfunctioning pancreatic neuroendocrine tumors. J Clin Endocrinol Metab

94:3640, 2009.)

A

B

2987 Multiple Endocrine Neoplasia Syndromes CHAPTER 388

Other Pancreatic NETs NETs secreting growth hormone–

releasing hormone (GHRH), GHRHomas, have been reported rarely

in patients with MEN 1. It is estimated that ~33% of patients with

GHRHomas have other MEN 1–related tumors. GHRHomas may be

diagnosed by demonstrating elevated serum concentrations of growth

hormone and GHRH. More than 50% of GHRHomas occur in the

lung, 30% occur in the pancreas, and 10% are found in the small intestine. Somatostatinomas secrete somatostatin, a peptide that inhibits

the secretion of a variety of hormones, resulting in hyperglycemia,

cholelithiasis, low acid output, steatorrhea, diarrhea, abdominal pain,

anemia, and weight loss. Although 7% of pancreatic NETs secrete

somatostatin, the clinical features of somatostatinoma syndrome are

unusual in patients with MEN 1.

Pituitary Tumors (See also Chap. 380) Pituitary tumors occur

in 15–50% of patients with MEN 1 (Table 388-1), and ~75% of these are

microadenomas (<1 cm diameter). The tumors occur as early as 5 years

of age or as late as the ninth decade. MEN 1 pituitary adenomas are

more frequent in women than men, in whom they are often macroadenomas (>1 cm diameter). There are no specific histologic parameters

that differentiate between MEN 1 and non–MEN 1 pituitary tumors.

Approximately 60% of MEN 1–associated pituitary tumors secrete prolactin, <25% secrete growth hormone, 5% secrete adrenocorticotropic

hormone (ACTH), and the remainder appear to be nonfunctioning,

with some secreting glycoprotein subunits (Table 388-1). However,

pituitary tumors derived from MEN 1 patients may exhibit immunoreactivity to several hormones. In particular, there is a greater frequency

of somatolactotrope tumors. Prolactinomas are the first manifestation

of MEN 1 in ~15% of patients, whereas somatotrope tumors occur

more often in patients aged >40 years. Fewer than 3% of patients with

anterior pituitary tumors will have MEN 1. Clinical manifestations

are similar to those in patients with sporadic pituitary tumors without

MEN 1 and depend on the hormone secreted and the size of the pituitary tumor. Thus, patients may have symptoms of hyperprolactinemia

(e.g., amenorrhea, infertility, and galactorrhea in women, or impotence

and infertility in men) or have features of acromegaly or Cushing’s

disease. In addition, enlarging pituitary tumors may compress adjacent

structures such as the optic chiasm or normal pituitary tissue, causing

visual disturbances and/or hypopituitarism. In asymptomatic patients

with MEN 1, periodic biochemical monitoring of serum prolactin and

insulin-like growth factor 1 (IGF-1) levels, as well as MRI of the pituitary, can lead to early identification of pituitary tumors (Table 388-3). In

patients with abnormal results, hypothalamic-pituitary testing should

characterize the nature of the pituitary lesion and its effects on the

secretion of other pituitary hormones.

TREATMENT

Pituitary Tumors

Treatment of pituitary tumors in patients with MEN 1 consists

of therapies similar to those used in patients without MEN 1 and

includes appropriate medical therapy (e.g., bromocriptine or cabergoline for prolactinoma; or octreotide or lanreotide for somatotrope

tumors) or selective transsphenoidal adenomectomy, if feasible,

with radiotherapy reserved for residual unresectable tumor tissue.

Associated Tumors Patients with MEN 1 may also develop carcinoid tumors, adrenal cortical tumors, facial angiofibromas, collagenomas, thyroid tumors, and lipomatous tumors.

Carcinoid Tumors (See also Chap. 84) Carcinoid tumors

occur in >3% of patients with MEN 1 (Table 388-1). The carcinoid

tumor may be located in the bronchi, gastrointestinal tract, pancreas,

or thymus. At the time of diagnosis, most patients are asymptomatic

and do not have clinical features of the carcinoid syndrome. Importantly, no hormonal or biochemical abnormality (e.g., plasma chromogranin A) is consistently observed in individuals with thymic or

bronchial carcinoid tumors. Thus, screening for these tumors is dependent on radiologic imaging. The optimum method for screening has

not been established. CT and MRI are sensitive for detec