D.
ENDOCRINE
68  Cancer of the Endocrine System
Ammar Asban, Anish J. Patel, Sushanth Reddy, Thomas Wang,
Courtney J. Balentine, and Herbert Chen
S UMMARY OF K EY P OI N T S
Thyroid Cancer
• The incidence of thyroid cancer
is increasing, and there are
approximately 33,500 new cases per
year in the United States.
• The incidence of differentiated
thyroid cancer is 14.3 per 100,000
people per year, with a female-to-
male ratio of more than 3 : 1.
• Differentiated thyroid cancer (DTC)
includes papillary thyroid cancer
(PTC), which accounts for 80% of all
thyroid cancers; follicular thyroid
cancer (FTC), which accounts for
10% to 20% of all thyroid cancers;
and a rare type, Hürthle cell cancer.
• Medullary thyroid cancer (MTC)
arises from the parafollicular C cells
and accounts for 1% to 2% of all
thyroid cancers.
• Anaplastic thyroid cancer is a rare,
but rapidly fatal, form of thyroid
cancer.
• Other histologic types of cancer,
such as lymphoma, sarcoma, and
metastatic cancers, can also be
found within the thyroid.
• Known risk factors for the
development of thyroid cancer
include radiation exposure and
iodine deficiency.
• Thyroid cancer can also run in
families or exist as part of familial
syndromes (Gardner, Cowden, and
Werner syndromes).
• More recently, the molecular
pathogenesis of thyroid cancer has
been investigated. The following are
the most widely studied molecular
markers for DTC to date:
○ RET/PTC rearrangement
○ BRAF
○ PAX8-PPARγ rearrangement
○ NRAS, KRAS and HRAS
1074
• Cancer with well-differentiated
histologic features has an excellent
5-year survival rate (>95%).
• Older age and extent of invasion are
related to prognosis.
• Lymph node involvement is
associated with higher recurrence
but has questionable impact on
survival.
• Multiple staging systems exist for
DTC.
• For Hürthle cell adenoma, larger size
(>6 cm) is predictive of malignancy.
• For poorly differentiated tumors,
lymph node metastases are common
in recurrence.
• Anaplastic cancers are extremely
aggressive, with 5-year survival rates
below 5%.
• The history should include radiation
exposure, family history, and
compressive symptoms (dysphagia,
hoarseness, pain or pressure) from
enlarging tumor.
• Concerning examination findings
include a fixed mass or
lymphadenopathy.
• Presented as incidental findings on
computed tomography (CT),
magnetic resonance imaging (MRI),
positron emission tomography (PET),
and ultrasound.
• Preoperative laboratory studies
include thyroid-stimulating hormone
(TSH) and thyroglobulin (Tg).
• Fine-needle aspiration (FNA) biopsy
is a key component of the workup of
thyroid nodules. The Bethesda
criteria classify FNA results and
determine the risk of cancer in the
nodule.
• Preoperative imaging should include
cervical ultrasound. CT is used when
aggressive variants are suspected, in
order to assist in operative
planning.
• Treatment begins with surgery. Most
thyroid cancers are treated with total
thyroidectomy. Compartment-
oriented neck dissection is added
when there is metastatic disease in
the cervical lymph nodes.
• Adjuvant therapy for differentiated
tumors is radioactive iodine
(iodine-131 [131I]).
• Patients must be prepared for
radioactive iodine ablation with low
iodine diet, withdrawal from thyroid
hormone replacement, or given
recombinant human thyroid hormone
(rhTSH) if there is no evidence of
metastatic disease.
• After surgery and radioactive
iodine, thyroxine suppression
prevents the growth of microscopic
disease.
• External beam radiation is used for
persistent, recurrent, anaplastic,
poorly differentiated tumors that are
not iodine avid.
• Chemotherapy is mainly palliative for
poorly differentiated or anaplastic
tumors. Traditional chemotherapy
has minimal response rates, but
newer, targeted therapies, such as
sorafenib, lenvatinib, and sunitinib,
are showing promise.
• Surveillance for recurrent thyroid
cancer includes measurements of
TSH, Tg, and anti-Tg antibodies in
addition to cervical ultrasound. The
schedule of these tests is tailored to
risk level.
• Treatment of recurrence can include
external beam radiation, targeted
therapies, or ultrasound-guided laser
ablation, depending on the iodine
avidity of the tumor.

Medullary Thyroid Cancer
• Medullary thyroid cancer (MTC)
accounts for 1% to 2% of all thyroid
cancers; 75% of cases are sporadic,
and 25% are familial (multiple
endocrine neoplasia [MEN] type 2,
familial medullary thyroid carcinoma
[FMTC]).
• The diagnosis is made by FNA with
calcitonin staining and/or washout.
RET testing can identify inherited
germline mutations. Cervical
ultrasound or CT scans assist with
operative planning. The tumor
markers calcitonin and
carcinoembryonic antigen (CEA) can
be useful in following patients
postoperatively for identifying
recurrence and metastases.
• At a minimum, treatment of clinical
MTC should consist of total
thyroidectomy plus central lymph
node dissection. Lateral neck
dissection is added when there are
clinically positive nodes in the
central neck and for high-risk
patients.
• Traditional chemotherapy is not
effective for metastatic MTC, but
newer, targeted therapies for
metastatic disease, such as
vandetanib and cabozantinib, have
shown some promise.
Adrenocortical Cancer
• The incidence of adrenocortical
cancer is 1 to 2 per million
people.
• Most adrenocortical cancers are
sporadic, but they can also occur as
part of familial syndromes such as
MEN1, Li-Fraumeni syndrome,
Beckwith-Wiedemann syndrome,
and Carney complex.
• Most are asymptomatic, but 40% to
60% are functional (hormone
production), and this may be the
presenting symptom(s).
• The diagnosis is by urinary or
plasma biochemical testing and
imaging: CT, fluorodeoxyglucose
(FDG)-PET.
• Often the diagnosis is not made
definitively until after resection of
suspicious masses, and pathologic
assessment provides definitive
diagnosis. FNA of adrenal masses is
rarely indicated.
• Surgery is the mainstay of treatment
for adrenocortical cancer and should
consist of en bloc resection of the
adrenal gland with adjacent organs
and tissue that is involved;
Cancer of the Endocrine System  •  CHAPTER 68 1075
cardiopulmonary bypass may be
necessary for caval involvement.
• Long-term surveillance, consisting of
physical examinations and CT scans,
is necessary to monitor for disease
recurrence.
• Mitotane alone or in combination
with other chemotherapeutic agents
improves recurrence-free survival.
• Radiotherapy may improve local
control, but there are no clear
recommendations.
• Hormonal control can also limit
disease spread and consists of
mitotane, ketoconazole, metyrapone,
and etomidate.
• Excision or reoperation is
recommended for recurrent or
metastatic disease.
• The prognosis is poor, with an
overall 5-year survival rate of less
than 40%.
Malignant Pheochromocytoma
• The incidence of malignant
pheochromocytoma (PCC) is 2 to 8
per 1,000,000 adults.
• Most malignant PCCs are sporadic,
but 10% are part of inherited
syndromes such as MEN syndromes,
neurofibromatosis type 1, von
Hippel-Lindau syndrome, and
succinate dehydrogenase gene
mutations.
• PCCs manifest with the classic triad
of functional tumors—headache,
tachycardia, and sweating—but they
are asymptomatic in more than 50%
of cases, incidentally discovered as
an adrenal mass.
• The diagnosis is established with
urinary or plasma fractionated
metanephrines and catecholamines.
• Tumors are localized with CT or MRI;
metaiodobenzylguanidine (MIBG) is
used to identify extraadrenal
metastases.
• Treatment begins with surgery to
resect the entire gland with clear
margins. Surgery can also be useful
in debulking for metastatic disease.
• Metastatic or unresectable disease
can be treated with 131I-MIBG or
chemotherapy.
• Radiotherapy is used for palliation in
bone and lymph node metastases.
• Medical therapy to prepare patients
for surgery or control symptoms of
catecholamine excess can include
phenoxybenzamine, nicardipine, or
metyrosine.
• Five-year survival ranges from 20%
to 50%.
Multiple Endocrine Neoplasia
Syndromes
• MEN1 manifests first with
hyperparathyroidism in patients in
their 30s and 40s. Other
manifestations include pituitary
tumors and neuroendocrine tumors
(NETs) of the pancreas (such as
gastrinoma) and upper
gastrointestinal tract.
• MEN1 is inherited in an autosomal
dominant fashion. Mutations in the
MENIN tumor suppressor gene
cause this disease, but expression is
variable.
• Treatment of parathyroid hyperplasia
is subtotal parathyroidectomy and
bilateral cervical thymectomy.
• MEN1 patients with pancreatic and
duodenal tumors are treated with
distal pancreatectomy, enucleation
of pancreatic head tumors,
duodenotomy, and mucosal
resection of multiple duodenal
tumors.
• MEN2A is characterized by
PCC, MTC, and primary
hyperparathyroidism
(hyperplasia).
• MEN2B is characterized by more
aggressive MTC, PCC, and mucosal
ganglioneuromas.
• The MTC in MEN2 syndromes arises
from C-cell hyperplasia and germline
RET mutations.
• Specific codon mutations in the RET
gene determine the disease
phenotype in MEN2 syndromes, and
help risk-stratify patients.
• Prophylactic thyroidectomy should
be offered to mutation carriers;
the timing of thyroidectomy is
determined by the specific codon
mutation.
• PCCs are often bilateral in MEN2
syndromes, but onset is
asynchronous. Consequently,
prophylactic adrenalectomy is not
indicated. Those MEN2 patients who
develop bilateral disease can be
treated with bilateral adrenalectomy
and hormone replacement or
cortical-sparing adrenalectomy.
Carcinoid Tumors
• The incidence of carcinoid tumors is
5.25 per 100,000 people.
• Tumors are identified with specific
immunohistochemical staining for
neuron-specific enolase (NSE) or
chromogranin A. Chromogranin A
also serves as a blood marker for
the disease.
Continued
1076 Part III: Specific Malignancies
• Several classification systems exist
for carcinoid tumors, including the
World Health Organization (WHO)
classification and the European
Neuroendocrine Tumor Society
(ENETS) staging system.
• Carcinoids arise from the Kulchitsky
cells in crypts of Lieberkühn of
the gut or disseminated in the
endobronchial mucosa, and are
classified by location.
• The diagnosis is made definitively
through tissue diagnosis, but urinary
5-hydroxyindoleacetic acid (5-HIAA),
serum NSE, and chromogranin A are
serum markers of the disease.
• CT or MRI can be used to localize
the carcinoid tumors, gallium-68
(68Ga)–DOTATATE PET-CT or
OctreoScan can be used, because
these tumors have somatostatin
receptors.
• The carcinoid syndrome occurs
in metastatic carcinoid and
presents as flushing, diarrhea, and
bronchoconstriction. Right-sided
valvular heart disease is also a
manifestation of the disease.
• Treatment begins with resection of
primary tumor with nodal
metastases.
• Debulking or metastasectomy is
beneficial for controlling symptoms
in patients with liver disease or bulky
disease.
• Radiation therapy is rarely used
for primary therapy but can be
palliative.
• Antihormonal therapy consists of
octapeptide analogues of
somatostatin; Sandostatin LAR is a
helpful, long-acting formulation
octapeptide analogue of
somatostatin.
• The liver is a common site for
metastatic carcinoid, and there are
several options for hepatic-directed
therapy, including surgery and
embolization (chemoembolization or
radioembolization).
• Metastatic disease can also be
treated with targeted agents or
emerging radionuclide therapy.
Pancreatic Neuroendocrine
Tumors
• The incidence of NETs is 2.4% to
5.8% per 100,000 people.
• Pancreatic neuroendocrine tumors
(pNETs) can be sporadic or inherited
(MEN).
• pNETs are diagnosed with CT or
MRI imaging; ultrasound or
endoscopic ultrasound (EUS)
examination can help guide biopsy.
• The ENETS staging system is
proposed to help stage pNETs.
• Insulinomas are diagnosed with
fasting hypoglycemia with elevated
plasma insulin levels; 10% are
malignant, and surgical resection
(enucleation) is curative.
• Glucagonoma is characterized by
migratory necrotizing erythema,
insulin-resistant diabetes, glossitis,
ileus, and constipation; 50% to 80%
are metastatic.
• Because of the higher rate of
metastatic disease, surgical
resection is curative in less than
one-third of patients with
glucagonoma.
• Somatostatinoma is characterized by
diabetes, diarrhea, and gallbladder
disorders.
• Treatment for somatostatinoma
includes cytoreductive surgery and
chemotherapy.
• Gastrinoma is characterized by ulcer
disease, in spite of adequate
treatment, and diarrhea.
• Gastrinoma is diagnosed through
hypergastrinemia with elevated basal
acid output or positive secretin test
result; tumors are localized with CT,
MRI, or octreotide scan. These
tumors are frequently metastatic.
• Targeted therapies such as
everolimus and sunitinib have been
approved by the US Food and Drug
Administration (FDA) for first-line
treatment of pNETs.
Parathyroid Carcinoma
• The incidence of parathyroid
carcinoma is 5.73 per 10 million
people.
• The etiology of parathyroid cancer
has recently been attributed to
pericentromeric inversion resulting in
overexpression of the cyclin D1
gene.
• In hyperparathyroidism–jaw tumor
syndrome, there are mutations in the
HRPT2 tumor suppressor gene
(parafibromin).
• Clinical characteristics of parathyroid
carcinoma include the constitutional
symptoms of primary
hyperparathyroidism, including
muscle weakness, fatigue, nausea,
vomiting, increased thirst, and
frequent urination, in addition to
bone pain and fractures.
• A neck mass occurs in 34% to 52%
but is uncommon in benign
parathyroid adenomas.
• In parathyroid carcinoma, serum
calcium is quite elevated (14.6–15.9)
with elevated serum parathyroid
hormone (PTH) (commonly 10-fold
higher than the upper limit of
normal).
• The diagnosis is made by means of
laboratory measurement of Ca and
PTH, and then technetium-99m
sestamibi scan and neck ultrasound
can be used to localize the tumor
with or without washout for PTH
measurement in FNA material.
• Pathologic features of parathyroid
carcinoma include local invasion and
lymph node metastases.
• Treatment of parathyroid carcinoma
should include en bloc resection of
the parathyroid mass with ipsilateral
thyroid lobe with or without
ipsilateral neck dissection followed
by postoperative calcium and
activated vitamin D supplementation.
• Medical therapy for hypercalcemia
precipitated by parathyroid
carcinoma should start with
hydration and loop diuretics;
calcimimetics (Cinacalcet) or
bisphosphonates can later be added
to lower the serum calcium levels.
• Adjuvant therapy includes
chemotherapy, such as dacarbazine,
5-fluorouracil (5-FU), or
cyclophosphamide; radiotherapy is
of limited efficacy.
• Patients with features of
hyperparathyroidism–jaw tumor
syndrome or a family history should
undergo genetic counseling and
HRPT2 testing.
• After surgery, one-third of patients
are cured, one-third have recurrence
after prolonged disease-free survival,
and one-third experience a short,
aggressive course; the 5-year
survival is 82.5%.

Unlike tumors found elsewhere in the body, cancers of the endocrine
organs can cause symptoms of hormonal excess in addition to mass
effect, obstruction, or pain from the mass itself. Therefore physicians
who care for patients with endocrine cancers must combat both the
physiologic manifestations and the neoplasia. Any of the endocrine
tumors can be part of a multitude of familial syndromes, so the clinician
caring for these patients must always keep this possibility in mind.
This chapter covers selected endocrine cancers and highlights some
of the unique challenges in treating such tumors. Many common
themes emerge. Diagnosis typically involves biochemical confirmation
of the endocrinopathy followed by imaging to locate the tumor(s).
Surgery plays a role in the initial treatment and often for recurrence
and palliation. Traditional chemotherapy is of limited use for endocrine
cancers, but newer, targeted therapies show more promise. This chapter
covers thyroid cancer, including medullary thyroid cancer (MTC),
adrenocortical carcinoma, malignant pheochromocytoma (PCC),
multiple endocrine neoplasia (MEN) syndromes, carcinoid tumors,
pancreatic neuroendocrine tumors (pNETs), and parathyroid carcinoma.
THYROID CANCER
Incidence
Thyroid cancer is the most common endocrine cancer. A spectrum
of biologic behavior exists, ranging from indolent, well-differentiated
tumors to extremely aggressive, poorly differentiated or anaplastic
cancers.1,2 Thyroid cancer is the most rapidly increasing malignancy
in the United States for both men and women. From 1980 to 2006,
the annual US thyroid cancer age-adjusted incidence rose from 4.33
to 11.03 cases per 100,000 population. This incidence increased by
2009 to 14.3 per 100,000.3 This is a nearly threefold increase in
incidence. The gender-adjusted incidence rose from 6.5 to 21.4 =
14.9 per 100,000 women and almost 4 times greater than that of
men, from 3.1 to 6.9 = 3.8 per 100,000 men.3 This increasing incidence
is attributed to improved detection of smaller tumors, mostly papillary
thyroid cancer, using high-resolution neck ultrasonography.4 This
change has been attributed mostly to the increase of papillary thyroid
cancer (PTC) incidence.5 A published report from a population-based
study states that the rapid increase in incidence of thyroid cancer is
attributed to occult cancer detected through neck imaging with stable
clinically detected thyroid cancer and disease mortality.6 Despite this
improved detection, the mortality rate remains unchanged at 0.5 per
100,000 population.7,8 Therefore, thyroid cancer presents a unique
challenge to the treating physician to manage patient expectations,
minimize potentially lifelong complications, use the appropriate surveil-
lance for follow-up, and identify patients with more aggressive, poorly
differentiated forms.
Classification
The most common type of thyroid cancer is PTC, representing 80%
of all cases. The second most common type is follicular thyroid cancer
(FTC), which represents 10% to 20% of all cases. Together, papillary
and follicular cancers are termed differentiated thyroid cancer (DTC),
and both arise from the thyroid follicular cells. MTC comes from the
parafollicular C cells. This neuroendocrine thyroid tumor represents
5% to 10% of all thyroid cancer cases and occurs in familial and
sporadic forms. Finally, anaplastic thyroid cancer (ATC) is one of the
most aggressive and rapidly fatal cancers. It can develop from DTC
that dedifferentiates over time, and it also arises de novo.1,2,9,10 The
first part of this section on thyroid cancer discusses DTC, and the
second part reviews MTC (Table 68.1, Fig. 68.1).
Etiology
External radiation exposure to the cervical region is one of the most
well-known causes of thyroid cancer. This risk is related to radiation
Cancer of the Endocrine System  •  CHAPTER 68 1077
Table 68.1  Histologic Classification of Thyroid
Cancers and Their Incidence
Tumor Histology Incidence (%)
Differentiated carcinomas 81–87
 Papillary
  Follicular variant of papillary
Follicular and Hürthle cell
 Medullary 6–8
 Anaplastic 5
 Lymphoma 1–5
 Metastatic <1
dose and age, and persists throughout life. Irradiation could result
from an external source used for diagnostic and therapeutic purposes
or from internal radiation from food or liquid that has radioactivity.
Historically, patients received radiation treatments for enlarged tonsils
or facial acne. Today, patients with cancer such as Hodgkin disease
might still receive radiation treatments. In addition, children exposed
to radioactive fallout from the Chernobyl (Russia) accident have
demonstrated an increased incidence of thyroid cancer.11,12 Based on
evidence from patients radiated for Hodgkin disease, doses of 40 Gy
are potentially carcinogenic.13 Epidemiologic studies have reported
that 7% to 9% of patients who received 5 to 10 Gy of external beam
radiation develop thyroid cancer.14 A lag time of 10 to 20 years usually
exists between exposure and diagnosis of thyroid cancer, although
much shorter periods have been reported (Table 68.2).14
Included in the environmental etiology for thyroid cancer is dietary
iodine content. A higher incidence of PTC exists in regions with
high dietary iodine content, such as the Pacific rim and Iceland.15
Iodine-deficient countries, in contrast, experience a higher incidence
of FTC in addition to benign thyroid goiters. Many factors con-
found these studies that link changes in DTC rates to iodine intake.
Ethnicity, selenium, goitrogen, and carcinogen intake likely play
causative roles.16
Increasing investigation into molecular markers that can distinguish
carcinoma from benign nodules has led to a greater understanding
of the genetic alterations in thyroid cancer. For example, 70% of
cancers found in Chernobyl survivors carried an RET and PTC gene
(RET/PTC) rearrangement. The fusion of the tyrosine kinase encoding
domain of the RET protein with a heterologous group of genes occurs
in 20% to 40% cases of PTC and is called the RET/PTC rearrangement.17
RET/PTC rearrangements are frequent in small, multifocal PTCs
accompanied by an inflammatory infiltrate, often seen in individuals
exposed to ionizing radiation and in children.18 BRAF is a member
of the RAF-MEK-ERK serine/threonine kinase-signaling cascade, and
a BRAF mutation is found in 40% to 60% of PTC cases.19,20 The
V600E BRAF point mutation or mutations in another member of
this signaling pathway, RAS, are frequent in cases of poorly differentiated
PTC or ATC.21 Analysis of 27 PTCs by Nikiforova and colleagues
showed that 70% harbored mutated genes, distributed among BRAF
(60%), PIK3A (11%), TP53 (7%), and NRAS (4%). In the same
study, the prevalence of mutated genes in follicular carcinoma was
NRAS, 25%; KRAS, 0.5%; HRAS, 0.2%; TSHR, 11%; TP53, 11%;
and PTEN, 0.2%.20 Most BRAF substitutions keep the protein in a
catalytically active form, resulting in constitutive activation of the
RAF-MEK-ERK signaling cascade and constant mitogenic activity.
A very high specificity of approximately 99% of BRAF V600E has
been estimated in data from multiple studies, with very low sensitivity
to rule out malignancy.22
A higher prevalence of BRAF V600E mutations were observed in
papillary thyroid microcarcinoma with lymph node metastasis and
tumor recurrence.23–25
1078 Part III: Specific Malignancies
A B
C D
Figure 68.1  •  Histologic patterns of thyroid cancer. (A) Papillary carcinoma. (B) Pure follicular carcinoma. (C) Anaplastic carcinoma. (D) Medullary
carcinoma.
The Ras proteins are plasma membrane guanosine triphosphatases
activated by growth factor receptors. Mutations that result in their
constitutive activation lead to oncogenesis. RAS mutations occur in
approximately 40% of follicular cancers and in a small portion of
PTCs, particularly the follicular variant of PTC.26,27 Similar to the
RET/PTC rearrangement, another interchromosomal translocation
occurs in FTC. The promoter element of the gene encoding paired
box 8 (PAX8) fuses with the coding sequence of the peroxisome
proliferator-activated receptor γ (PPARγ) gene in 35% of FTCs.21,28,29
The functional consequences of the PAX8/PPARγ rearrangement remain
unclear. RAS mutations are also highly prevalent in FTC, but Nikiforova
and colleagues found that RAS and PAX8/PPARγ rearrangements are
mutually exclusive, suggesting that these are two distinct molecular
pathways for FTC development.21
For diagnostic accuracy of molecular markers, especially for
indeterminate thyroid nodules, multiple panels have been expanded
to include mutational/translocational BRAF, NRAS, HRAS, and KRAS
point mutations, in addition to RET/PTC1 and RET/PTC3, with
or without PAX8/PPARγ rearrangements.30–34 TERT promoter mutations
have been identified in 2% to 10% of sporadic PTCs.35 They may
coexist with the V600E BRAF mutation in PTC and tend to be more
aggressive.36
Aside from these acquired genetic lesions, some forms of DTC
are also inherited. DTC is seen in familial syndromes such as Gardner
syndrome, Cowden syndrome, and Werner syndrome.37,38 Familial
nonmedullary thyroid cancer (FNMTC), in which two or more
first-degree relatives have been diagnosed with DTC in the absence
of another syndrome, exhibits autosomal dominant behavior with
incomplete penetrance and variable expressivity.38–40 Linkage analyses
have identified several candidate genes for FNMTC, including TCO1,
MNG1, fPTC/PRN, and NMTC1, but a single responsible gene has
not been identified.41–44 Evidence has shown that 5% to 10% of DTCs
have familiar occurrence.5 Compared with sporadic DTC, FNMTC
is more aggressive with increased recurrence and decreased disease-free
survival, local invasion, multicentricity, lymph node metastases, invasion
to surrounding structures, and combination with chronic lymphocytic
thyroiditis.45,46 However, in the absence of a suitable genetic test,
families cannot be screened, and FNMTC is difficult to distinguish
from sporadic DTC.47
Classification and Prognosis
DTCs are divided broadly as papillary or follicular. Follicular variant
PTC has features of both PTC and FTC but is classified as an PTC
subtype (see Table 68.1 and Fig. 68.1A). In general, well-differentiated
PTC has an excellent prognosis, with 5-year survival greater than
97%.7 Smaller tumors carry a better prognosis than larger tumors.
PTCs smaller than 1 cm are called papillary microcarcinomas and have
been reported in 10% to 30% of autopsy studies.48–50 In the past,
these tumors were incidentally detected in thyroidectomy specimens,
but they are now detected with increasing frequency with high-
resolution ultrasonography. They are believed to have an excellent
prognosis, with a structural disease recurrence rate of 1% to 2% in
unifocal PTCs and 4% to 6% in multifocal PTCs.51,52 However, some
may behave more aggressively than previously appreciated, and manage-
ment remains controversial.53,54
Age is another important determinant of prognosis in DTC. Older
patients tend to have more poorly differentiated, aggressive variants
and are less likely to respond to radioactive iodine (RAI). In these
cases, death results from local invasion and extensive metastases.
Therefore the completeness of resection and extrathyroidal extension
are two prognostic indicators used in many staging systems for DTC.55,56
The role of lymph node metastases in determining DTC-specific
survival remains controversial. Lymph node involvement is common
 Cancer of the Endocrine System  •  CHAPTER 68 1079

Table 68.2  Risk Factors for Malignancy in Nodular Table 68.3  TNM Classification of Malignant
Thyroid Tumors of the Thyroid Gland
LOW RISK ↔ HIGH RISK PRIMARY TUMOR (T STAGE)
Factor 1 2 3 4 5 Tx Tumor cannot be assessed
Age T0 No clinical evidence of tumor
Elderly • T1 Tumor ≤2 cm limited to the thyroid
Child • T2 Tumor >2 cm and <4 cm limited to the thyroid
Sex T3 Tumor ≥4 cm limited to the thyroid or any tumor with
minimal extrathyroid extension
Male •
T4a Tumor of any size extending beyond the thyroid capsule
Female • to invade the subcutaneous soft tissues, larynx, trachea,
Low-dose radiation in childhood • esophagus, or recurrent laryngeal nerve
Family history • T4b Tumor that invades prevertebral fascia or encases
Cystic mass • carotid artery or mediastinal vessels
Solid mass • ANAPLASTIC CARCINOMASa
Multiple masses • T4a Intrathyroidal—surgically resectable
Solitary mass • T4b Extrathyroidal—surgically unresectable
Growing mass •
REGIONAL LYMPH NODES (N STAGE)
Stable mass •
Nx Regional nodes cannot be assessed
Hot scan •
N0 No palpable nodes
Cold scan •
N1 Regional nodal metastases
Warm scan •
N1a Level VI nodes (pretracheal, paratracheal, prelaryngeal)
Fine-needle aspiration (−) •
N1b Metastasis to unilateral, bilateral, or contralateral cervical
Fine-needle aspiration (+) • or superior mediastinal nodes
Associated cervical adenopathy •
DISTANT METASTASES (M STAGE)
Complete resolution in response to •
thyroid suppression Mx Metastases cannot be assessed
Partial resolution in response to • M0 No evidence of distant metastases
thyroid suppression M1 Distant metastases present
No response to suppression •
a
All anaplastic carcinomas are considered T4 tumors.
Modified from Sessions RB, Diehi WL. Thyroid cancer and related nodularity. Modified from Greene FL, Page DL, Fleming ID, et al, eds. AJCC Cancer Staging
In: Myers E, Suen J, es. Cancer of the Head and Neck. 2nd ed. New York: Churchill Manual. 6th ed. New York: Springer-Verlag; 2002.
Livingstone; 1981:766.

in PTC, but the exact incidence of lymph node metastases depends
on how it is defined. Palpable disease in the lymph nodes is present
in 5% to 10% of patients with PTC, but ultrasound detects pathologi-
cally positive lymph nodes in 30% of patients.57,58 Ultrasound features
that are associated with thyroid cancer include nodule hypoechogenicity
compared with the surrounding structures, microcalcifications, irregular
margins, and taller-than-wide shape as measured on a transverse view.5
Only 2% of patients with FTC have lymph node metastases because
the route of spread is mostly hematogenous, but treatment guidelines
and retrospective studies frequently consider PTC and FTC together.
Routine histologic examination of lymph nodes reveals DTC in 20%
to 50% of patients (particularly papillary carcinoma), but when more
detailed inspection is performed, up to 90% of patients with DTC
will have lymph nodes with microscopic disease, smaller than 2 mm.59,60
An increasing amount of high-quality evidence supports sonographic
survey of cervical lymph nodes in all patients with thyroid nodules.5
Historically, lymph node involvement was believed to increase local
recurrence without affecting survival, and therefore surgeons took a
conservative approach to lymph node dissection for DTC. Wada and
colleagues demonstrated that patients with pathologically positive
lymph nodes had a recurrence rate of 16.3% compared with 0% in
patients without pathologically positive lymph nodes.61 Whether
metastatic lymph nodes are evident preoperatively appears to be
an important factor determining recurrence. For example, Ito and
colleagues found that if metastatic lymph nodes were not seen
preoperatively, then the risk of nodal recurrence was only 1.5%. Of
note, in this study of 590 patients with microcarcinomas, 40% of
patients had lateral neck lymph node metastases identified histologically
after prophylactic neck dissection.62 Hence, lymph node metastases
do affect recurrence, and clinically apparent nodes are more important
than pathologically positive nodes. The impact of lymph nodes on
survival is less clear. Large series and population-based studies have
suggested that there is a small but significant effect on survival.63,64
From the Surveillance, Epidemiology, and End Results (SEER)
database, comprehensive analysis showed that patients younger than
45 years with lymph node metastasis had small but significant risk of
death compared with younger patients with no lymph node involve-
ment.65 Because of the questionable effect on mortality, lymph node
status is not included in all of the staging systems available for DTC.
For example, the AGES system considers age, grade, extrathyroidal
extension, and size.66 The AMES system uses age, distant (non–lymph
node) metastases, extent of primary tumor, and size.67 Some, such as
the MACIS system (metastases, age, complete excision, invasion, and
size), also account for the adequacy of surgical treatment.68 Alternatively,
staging systems developed by the Ohio State University,69 the European
Organisation for Research and Treatment of Cancer (EORTC),70 the
National Thyroid Cancer Treatment Cooperative Study (NTCTCS),71
and the American Joint Committee on Cancer (AJCC)72 all do consider
lymph node status. The AJCC staging system is the most widely used
(Table 68.3). It is also known as the TNM system because it considers
1080 Part III: Specific Malignancies

and colleagues: “poorly differentiated thyroid carcinoma is a concept

Table 68.4  Staging of Thyroid Cancer proposed to include carcinomas of follicular thyroid epithelium that
Stage TNM Stage TNM retain sufficient differentiation to produce scattered small follicular
structures and some thyroglobulin (Tg), but generally lack the usual
PATIENTS YOUNGER THAN MEDULLARY THYROID morphologic characteristics of papillary and follicular carcinoma.”82
45 YEARS CANCER These tumors include insular, large cell, tall cell, columnar cell, solid,
I Any T, any N, M0 I T1, N0, M0 and diffuse sclerosing variants.1,82 In patients with these variants, the
II Any T, any N, M1 cancer tends to recur and metastasize. Furthermore, dedifferentiation
II T2–3, N0, M0
of thyroid cancers leads to underexpression or disordered assembly of
PATIENTS AGE 45 YEARS OR III T1–3, N1a, M0 the sodium-iodide symporter, decreasing the usefulness of RAI for
OLDER IVA T4a, N0–1a, M0 treating micrometastatic disease or detection of metastases.83 For these
I T1, N0, M0 T1–4a, N1b, M0 reasons, poorly differentiated thyroid cancers have a 51% disease-free
II T2, N0, M0 IVB T4b, any N, M0 survival rate and a 70% cause-specific survival rate at 5 years.1,81
III T3, N0, M0 IVC Any T, any N, M1 Primary lymphoma of the thyroid is not as common as DTC.
T1–3, N1a, M0 Older women or patients with Hashimoto thyroiditis are at highest
ANAPLASTIC CANCER risk for developing thyroid lymphoma.84 These tumors typically manifest
IVA T4a, N0–1a, M0
IVA T4a, any N, M0 as a rapidly expanding mass causing pain and compressive symptoms.
T1–4a, N1b, M0
IVB T4b, any N, M0 Flow cytometry of cytologic specimens can sometimes be used to
IVB T4b, any N, M0 make the diagnosis, but the condition might be mistaken for Hashimoto
IVC Any T, any N, M1
IVC Any T, any N, M1 thyroiditis. Consequently, a core biopsy is sometimes necessary when
this diagnosis is suspected. Most are B-cell lymphomas treated with
From Greene FL, Page DL, Fleming ID, et al, eds. AJCC Cancer Staging Manual. chemotherapy and radiation. Surgery is occasionally needed for pal-
6th ed. New York: Springer-Verlag; 2002. liation.84 Prognosis depends on the histologic subtype.

tumor size (T), lymph node metastases (N), and distant metastases
(M). Like many of the other thyroid cancer staging systems, it also
considers age, with two different classifications for those younger and
older than 45 years. In those younger than 45 years, patients with
lymph node metastases are classified as stage I unless they have distant
metastases (stage II) (Table 68.4).72
It is worth noting some important ways in which FTC differs
from PTC (see Table 68.1, Fig. 68.1B). Pure follicular carcinoma
tends to occur more in older patients, and it carries a worse prognosis
than PTC. Follicular carcinoma is more common in women than in
men by approximately three times.73 Even when the disease is confined
to the thyroid, 5% to 15% of patients ultimately die from the disease,
although survival still extends decades as in PTC.74 In addition to the
prognostic factors common to the aforementioned DTC staging systems,
prognosis in FTC depends on the degree of capsular and vascular
invasion. Minimally invasive tumors are grossly contained within the
thyroid but have microscopic foci of invasion into the capsule. Invasive
tumors carry a worse prognosis and invade the capsule and vessels.75,76
Hürthle cell tumors of the thyroid are often classified with follicular
cancer because they are derived from the follicular cell. Both adenomas
and carcinomas of the Hürthle cell can occur, and differentiating
them by cytologic assessment is difficult, as it is with follicular
lesions.77,78 Capsular and vascular invasion distinguish carcinoma from
adenomas. Large Hürthle cell cancers (>2 cm) have a higher recurrence
rate, ranging from 21% to 59%.77,79 Furthermore, Hürthle cell cancers
do not always concentrate iodine. For these reasons, Hürthle cell
carcinoma carries a worse prognosis compared with DTC. Adenomas
have an excellent prognosis after resection and less than 2.5% dem-
onstrate malignant behavior, but resection is recommended for larger
adenomas because size is a major predictor of malignancy.79,80
As follicular or papillary cancers progress or dedifferentiate, their
prognosis becomes much worse. Anaplastic cancers are at the least
differentiated end of the spectrum and represent one of the most
aggressive cancers, with 5-year disease-free survival and cause-specific
survival rates of 0%.81 ATC can arise from well-differentiated tumors,
or it can also develop de novo (see Fig. 68.1C).81 A group of tumors
falls between well-differentiated thyroid cancers and anaplastic cancers.
These cancers, called poorly differentiated thyroid cancers, are intermediate
in terms of their histologic appearance and their biologic behavior.1
Although the literature remains inconsistent about what constitutes
poorly differentiated cancer, the best definition comes from Burman
Diagnosis
Just as with a newly discovered mass anywhere else in the body, the
workup of a thyroid nodule begins with a thorough history and physical
examination. A strong family history of thyroid cancer or cancer
syndromes or a history of radiation exposure to the head and neck
or total-body radiation for bone marrow transplantation85 should raise
the suspicion of thyroid cancer. Rapid growth and/or hoarseness with
compressive symptoms may indicate that the thyroid nodule is thyroid
lymphoma or a poorly differentiated thyroid cancer.1,2,14 On examina-
tion, malignant nodules are harder and fixed, whereas a nodule that
is rubbery or soft and moves easily with deglutition is reassuring but
not diagnostic of a benign nodule. Nonpalpable nodules have the
same risk of malignancy as palpable nodules of the same size.86–89
Cervical lymphadenopathy also increases the likelihood that a thyroid
nodule is malignant.2,90
Laboratory Studies
Because the management of patients with functional thyroid nodules
differs from that of patients with nonfunctional nodules, obtaining
a thyroid-stimulating hormone (TSH) measurement early in the workup
of a thyroid nodule can efficiently identify patients with a nodule and
hyperthyroidism. In this subset of patients with a suppressed TSH,
an iodine-123 (123I) scan can distinguish a solitary toxic nodule from
a toxic multinodular goiter and Graves disease. A solitary hyperfunction-
ing nodule is rarely malignant, and fine-needle aspiration (FNA) biopsy
or further cancer workup is rarely necessary. The one exception is that
functioning nodules in children do carry a higher risk of malignancy.91
If thyroid radionuclide scanning is undertaken, “cold” nodules should
undergo FNA biopsy because 10% to 20% of cold nodules are
malignant.92,93 A higher serum TSH is an independent risk factor for
predicting malignancy and is associated with more advance disease.94,95
Other laboratory tests can be helpful once the diagnosis of a certain
type of thyroid cancer has been made. For example, measuring serum
Tg in patients with DTC can assist with the long-term follow-up of
patients treated for DTC.96–98 Although Tg levels can be elevated in
patients with DTC, the test is insensitive and nonspecific for diagnosing
cancer, elevations in Tg can occur in benign thyroid disorders, and
the American Thyroid Association (ATA) guidelines do not recommend
routine preoperative Tg measurement for patients with DTC. After
a total thyroidectomy, however, elevations in Tg can reliably indicate
recurrent or metastatic disease.5 Different threshold Tg levels can
indicate recurrence depending on the concomitant TSH level. It should

be emphasized, however, that there is no role for Tg measurement in
the initial evaluation of thyroid nodules.
Measurement of serum anti–thyroid peroxidase (TPO) antibod-
ies may be helpful in patients with high TSH levels suggestive of
autoimmune thyroiditis; however, routine measurement is not necessary.
Fine-Needle Aspiration Biopsy
FNA biopsy remains the gold standard for evaluating thyroid nodules.
Most clinical practice guidelines recommend FNA biopsy for nodules
greater than 1 cm in largest dimension with a high to intermediate
sonographic pattern.5,92,99 Biopsy can be performed on nodules larger
than 1.5 cm with few suspicious characteristics.5 For nodules larger
than 1 cm with suspicious sonographic features of extrathyroidal
extension or associated lymphadenopathy, FNA should be performed
in selected patients such as those with family history of thyroid cancer.100
When the FNA result is clearly benign or malignant, then the decision
for further treatment, including thyroidectomy, becomes evident. The
false-negative rate for FNA biopsy is 1% to 3% (Table 68.5). The
false-negative rate increases to 10% to 15% when the nodule is large
(>4 cm).99,101 Other clinical scenarios in which the clinician should
not always trust a benign FNA result include patients with a family
history of thyroid cancer, patients with a history of radiation exposure,
and cystic nodules.102 Ultrasound guidance can improve the accuracy
of FNA biopsy by confirming that the nodule is actually being sampled
and by enabling targeting of the most suspicious portions of the
nodule (e.g., the wall of a cyst). This is especially true for nondiagnostic
cytologic findings (>25%–50% cystic component) or nonpalpable or
posteriorly located nodules.103,104
Nodules that do not meet FNA criteria, such as suspicious sub-
centimeter nodules in individuals older than 60 years, single nodules
with well-defined margins, and nodules with a rim of normal thyroid
parenchyma that is larger than 2 mm, can be observed.100
FNA results are classified according to the Bethesda criteria, which
indicate the risk of malignancy (see Table 68.5). One of the limitations
of cytologic evaluation of thyroid nodules is that it cannot distinguish
between adenoma and carcinoma in follicular lesions.92,101 Therefore
lobectomy with permanent histology may be the best way to make a
definitive diagnosis in follicular or indeterminate lesions. Furthermore,
20% to 30% of FNA results fall into the category of indeterminate
cytologic findings, such as atypia of undetermined significance (AUS)
or follicular lesion of undetermined significance (FLUS).105 Currently,
many centers have turned to molecular analysis of FNA specimens
to help distinguish follicular lesions. Cytologic specimens are analyzed
for a panel of mutations, including BRAF, RAS, RET/PTC, and PAX8-
PPARγ rearrangements. The seven-gene mutational panel, most useful
when surgery is favored, has sensitivity that ranges from 44% to
100%.32–34 Although this is an exciting area of research, the clinical
usefulness of the various gene panels has varied, and more prospective
data are needed.19,21,28,81,106
Table 68.5  The Bethesda System for Thyroid Cytopathology
Category Risk of Malignancy (%)
Nondiagnostic or unsatisfactory
Benign
Atypia of undetermined significance (AUS) or follicular
lesion of undetermined significance (FLUS)
Follicular neoplasm or suspicious for follicular neoplasm
Suspicious for malignancy
Malignant
a
Lobectomy also can be considered depending on clinical or sonographic characteristics.
FNA, Fine-needle aspiration.
Cancer of the Endocrine System  •  CHAPTER 68 1081
Testing for molecular markers from FNA aspirates could be
conducted for FLUS, AUS, or follicular neoplasm. These are BRAF
and RAS mutational status, high-density genomic data for molecular
classification (an FNA-trained mRNA classifier), and FNA-trained
miRNA classifier combined with molecular markers of malignancy.107,108
Patient counseling regarding the potential benefits and limitations and
the long-term clinical implications of the molecular testing should
be done according to the ATA guidelines. The guidelines also recom-
mend that these tests should be performed in Clinical Laboratory
Improvement Amendments/College of American Pathology (CLIA/
CAP)–certified molecular laboratories or the international equivalent.5
Imaging
Not only can ultrasonography improve the accuracy of FNA biopsy,
but it is also an important tool in evaluation of thyroid nodules
because it is used to measure the size and features of the nodule and
it can also reveal additional nonpalpable nodules. Ultrasound examina-
tion alone can increase the clinician’s suspicion for malignancy if the
nodule has fine microcalcifications, irregular borders, chaotic vascular
patterns or peripheral vascularity, cystic aspect, or hyperechogenicity.109
In addition, ultrasound scanning can be used to evaluate the lymph
nodes in both the central and the lateral neck compartments, which
may prompt additional FNA biopsy of suspicious lymph nodes or
result in alterations in the surgical plan. Although ultrasound examina-
tion is highly operator dependent, it is noninvasive and does not
involve any radiation or contrast agent risk to the patient. High-
resolution ultrasonography can also demonstrate extracapsular invasion
and subtle lymph node involvement.104,110–115 Consequently, ultraso-
nography is the preferred method to evaluate the thyroid and cervical
lymph nodes. Although routine screening is not recommended for
all patients, those with a strong family history or radiation exposure
can undergo ultrasound screening for thyroid nodules. Use of positron
emission tomography (PET) and/or computed tomography (CT) scan
is helpful for identifying lung or bone tumors in patients at risk for
metastases.112,116
Highly aggressive cancers that may invade local structures, extend
into the chest, or demonstrate poorly differentiated cytologic features
require careful preoperative planning. In such cases, CT becomes a
helpful preoperative imaging study in planning en bloc resection of
other organs aside from the thyroid, understanding the extent of
vascular involvement, determining if a thoracic incision is necessary,
and planning for reconstruction.1,112,116,117
Chest CT or PET-CT imaging studies performed for other medical
indications often reveal thyroid nodules incidentally. PET scans
demonstrate thyroid masses during the workup and staging of other
cancers. This subset of incidentally discovered thyroid nodules deserves
special attention because up to 50% of fluorodeoxyglucose (FDG)-avid
thyroid nodules will contain thyroid cancer. Therefore, PET-positive
thyroid nodules should undergo FNA biopsy.
Recommended Management
1–4 Repeat FNA with ultrasound guidance
0–3 Clinical follow-up
5–15 Repeat FNAa
15–30 Lobectomy
60–75 Lobectomy with or without frozen section or
total thyroidectomy
97–99 Total thyroidectomy
1082 Part III: Specific Malignancies
Treatment
Treatment of DTC involves a surgeon, an endocrinologist, a nuclear
medicine specialist, and, occasionally, a radiation oncologist. A
multidisciplinary approach best serves patients with DTC.
Surgery
The extent of surgery for DTC remains controversial. This is especially
true for small, encapsulated, well-differentiated tumors, and tumors
smaller than 1 cm (microcarcinomas). These are discussed further
later, but for most DTCs 4 cm or larger that were diagnosed preop-
eratively, most clinicians recommend a total thyroidectomy.5 Controversy
still exists for lesions larger than 1 cm and smaller than 4 cm with
low- or intermediate-risk features. Contrary to the previous guideline
recommendations,118 the new guidelines5 recommend either total
thyroidectomy or lobectomy for treatment. Thyroid lobectomy may
be sufficient for this type of lesion without extrathyroidal extension
and with no evidence of lymph node metastasis. This is based on
evidence from properly selected patients that showed similar clinical
outcomes with either surgical plan.119–123 Furthermore, lobectomy can
obviate the need for exogenous thyroid hormone. Finally, because the
current practice for follow-up depends more on ultrasound findings
and Tg measurement than on whole-body RAI, total thyroidectomy
is no longer needed to justify postoperative RAI.5 Analysis of 5432
patients with PTC from the SEER database found no difference in
10-year overall survival between total thyroidectomy (4612 patients)
and thyroid lobectomy (820 patients).122 Results from two other
single-center studies showed excellent survival in properly selected
patients who underwent lobectomy.119,123 Without evidence of high-risk
features, initial lobectomy of 1- to 4-cm thyroid carcinomas is more
cost-effective after 3 years of follow-up.124 On the other hand, the
rationale for total thyroidectomy is based on tumor biology and current
treatment modalities. DTC, especially PTC, tends to be multicentric,
with up to 80% of patients having multiple tumor foci and 60%
having bilateral disease when a thorough pathologic examination of
the contralateral lobe was performed.10,53,112 A study showed that 43%
of patients who underwent thyroidectomy for 1- to 4-cm thyroid
cancers had high-risk characteristics that would have necessitated
complete thyroidectomy if lobectomy had been used as initial treat-
ment.125 A total thyroidectomy as the initial procedure obviates the
need for reoperative surgery to remove the contralateral lobe should
a recurrence become detected. Second, experienced thyroid surgeons
can safely perform a total thyroidectomy, with permanent complications
such as recurrent laryngeal nerve injury and hypoparathyroidism
occurring at a rate of less than 2%.54,117 RAI therapy for ablation of
microscopic disease becomes most effective when the thyroid remnant
is small or absent. Tg measurement and radioiodine whole-body
scanning are highly sensitive modalities for detection of recurrent or
metastatic disease, but these two methods are most effective when no
thyroid tissue remains in the neck.2,126
Most low-risk cancers carry an excellent prognosis regardless of
the extent of thyroidectomy, and there are no randomized prospective
trials comparing total thyroidectomy and thyroid lobectomy in this
group of patients. In addition, radioiodine may have limited usefulness
in low-risk patients.10,53 For these reasons, some researchers favor thyroid
lobectomy in low-risk patients. For example, Shaha and colleagues
have reported 20-year follow-up findings in 465 patients with low-risk
DTC. Although the lobectomy group had more local recurrence
compared with the total thyroidectomy group (4% versus 1%), there
was no statistical significance.127 Similarly, other groups have also
failed to demonstrate any significant effect on survival.128–130 In contrast,
large retrospective series have demonstrated improvement in recurrence
rates for total thyroidectomy compared with less extensive opera-
tions.69,131–133 In a frequently cited study, Mazzaferri and colleagues
reported on 1355 patients with a mean follow-up of 15.7 years. Patients
treated with total thyroidectomy experienced significant improvements
in recurrence rate (26% versus 40%, P < .02) and mortality rate (6%
versus 9%, P = .02) compared with less extensive resections.134 Owing
to concerns regarding the accuracy of risk stratification and complica-
tions in these retrospective studies, current guidelines recommend
lobectomy for small (<4 cm), unifocal, well-differentiated tumors with
no lymph node metastases or extrathyroidal extension.5
Another hotly debated topic related to the extent of initial surgery
for DTC is the role of prophylactic central neck dissection. The most
recent guidelines are consistent with the 2009 guidelines, which state
that “prophylactic central neck dissection may be performed, especially
in patients with advanced primary tumors (T3 or T4) or clinically
involved lymph nodes” and “total thyroidectomy without prophylactic
central neck dissection may be appropriate for small (T1 or T2),
noninvasive, clinically node-negative patients.”5,97
The central neck lymph nodes are also classified as level VI lymph
nodes and include the paratracheal, perithyroidal, and precricoid lymph
nodes. These nodes are found along and behind the recurrent laryngeal
node, and frequently surround the lower parathyroid gland. Although
the level VI lymph nodes contain macroscopic disease in 10% of
cases, when they are removed prophylactically, 32% to 69% of patients
will have microscopic metastases.135–137
Proponents of prophylactic central neck dissection argue that the
initial operation is the safest time to remove central neck lymph nodes
to prevent local recurrences and the complications associated with
reoperative surgery in the central neck. Wada and colleagues found
the recurrence rate in patients treated with therapeutic lymph node
dissection to be 21%, whereas patients who underwent prophylactic
neck dissection experienced a recurrence rate of only 0.43%. Important
to note, those patients without clinically overt nodal disease who did
not undergo prophylactic central neck dissection also experienced a
very low recurrence rate of 0.65%. Hence, the absolute differences
in recurrence are minuscule.61 Several other studies also have supported
the concept that microscopically positive lymph nodes rarely progress
to recurrence, especially after postoperative RAI ablation.138–140 Clinically
evident lymph node metastases place patients at higher risk for recur-
rence, and these patients clearly benefit from therapeutic lymph node
dissection. Prophylactic central neck dissection reduces an already low
recurrence rate and potentially eliminates or reduces the need for RAI
but is also associated with risks such as hypoparathyroidism. The
risk-to-benefit ratio may favor prophylactic central neck dissection in
a subset of patients, but the putative risk factors that define such a
subset remain unknown.112,141,142
Evidence supports a selective approach of prophylactic level VI
node dissections in patients with clinically or radiographically involved
lymph nodes or intraoperative detection of metastatic lymph nodes
(cN1).143–145 Thyroidectomy begins with proper patient positioning
in the semirecumbent position with the neck extended (Fig. 68.2).
A transverse, curvilinear incision is made in a suitable skin crease at
or beneath the level of the cricoid cartilage. Traditionally a Kocher
collar incision was used, but this requires a very large dissection
superiorly to reach the upper pole of the thyroid, placing the patient
at risk for postoperative seroma. Intraoperative ultrasound guidance
can help in assessing the upper extent of the gland and placing the
incision appropriately. Superior and inferior subplatysmal flaps are
raised to create a working space around the thyroid. The strap muscles
are divided in the median raphe and are retracted laterally. It is rarely
necessary to transect the strap muscles, but this can be accomplished
if the tumor is large or adherent to the overlying muscles. The peri-
thyroidal soft tissue is swept off the gland bluntly to identify the
boundaries of the thyroid. Because the thyroid is most fixed at the
upper pole, these vessels are divided first. Much of this can be
accomplished by using energy devices such as the Harmonic scalpel
or LigaSure, but in larger vessels clips and/or ties may be required.
The upper pole vessels should be ligated close to the thyroid capsule
to avoid injuring the external branch of the superior laryngeal nerve.
In addition, the surgeon should remain vigilant for the upper para-
thyroid gland, which is frequently located near the upper pole vessels.
Next, the thyroid gland is reflected medially. To accomplish this, the
 Cancer of the Endocrine System  •  CHAPTER 68 1083

Sternohyoid Superior thyroid

muscle vessels

Thyroid
Internal
cartilage
jugular
vein

Recurrent
laryngeal
Incision Vagus nerve
nerve Inferior
Sternocleidomastoid Common thyroid
muscle carotid artery artery
A B C

D E
Figure 68.2  •  Thyroidectomy. (A) The patient is placed with the neck in extension. The thyroid is approached through a Kocher collar incision, which
is commonly made approximately 2 cm superior to the sterna notch. (B) The strap muscles are divided in the midline to expose the thyroid gland. (C) The
strap muscles are retracted laterally and the thyroid is retracted medially, exposing the structures of the midneck. The recurrent laryngeal nerve can be seen
lying within the tracheoesophageal groove. (D) The superior pole vessels are individually clamped and ligated as they enter the thyroid gland. Inferior thyroid
vessels, in addition to the thyroidea ima vessels, are individually suture-ligated. (E) The dissection is completed by dissection of the thyroid gland off the
trachea. The isthmus is then transected and can be oversewn with a suture for hemostasis.

middle thyroid vein is ligated. In addition, dividing the thyroid isthmus
can also facilitate medial rotation, assuming that the tumor is not
located within the isthmus. Before any structures along the medial
border of the gland are divided, the recurrent laryngeal nerve must
be identified and its course dissected. The nerve is found medial to
the upper parathyroid gland and lateral to the lower parathyroid. The
parathyroid glands must also be identified and dissected free from the
thyroid on an intact vascular pedicle. Once the recurrent laryngeal
nerve has been identified, the branches of the inferior thyroid artery
can be divided along the thyroid capsule. The inferior pole also is
mobilized with a combination of blunt dissection and ligation of the
inferior thyroid artery. The thyroid is then dissected off the anterior
surface of the trachea with electrocautery or other energy devices to
divide the small vessels contained within the ligament of Berry. Perform-
ing the identical procedure on the contralateral lobe completes a total
thyroidectomy.
Before passing the specimen off the field, the surgeon should examine
it to make sure that there is no parathyroid tissue adherent to the
gland. Any inadvertently removed parathyroid tissue can be finely
minced and reimplanted into either the sternocleidomastoid or the
strap muscles. Frozen section of a biopsy specimen of this tissue can
be used to distinguish among fat, parathyroid, or lymph node; this
will also help in avoiding autotransplanting cancer-bearing lymph
nodes back into the patient. Two or three pockets are created within
the muscle, and the minced parathyroid tissue is divided among these
pockets. Each pocket should be marked with permanent suture so
that it can easily be found in a reoperative setting.
Preoperative FNA or intraoperative frozen section can be used to
confirm that enlarged lymph nodes seen on ultrasound harbor metastatic
disease. Cytologic or pathologic confirmation of lymph node metastases
should prompt the surgeon to perform a compartment-oriented lymph
node dissection. Lymph node sampling or “berry-picking” should be
avoided, because this leaves behind lymph nodes that likely contain
microscopic disease, which then become more difficult to excise in a
reoperative setting.
Although “skip” metastases directly to the lateral compartment
can occur in PTC, the central neck nodes (level VI) are usually the
first nodes to receive drainage from the thyroid (Fig. 68.3). The
boundaries of the central neck are the carotid sheathes laterally, the
hyoid bone superiorly, and the innominate artery inferiorly.146
Lymphadenectomy in this area requires skeletonizing the recurrent
laryngeal nerve along its entire cervical course, and removing all the
fibrofatty tissue along the trachea. Frequently, the lower parathyroid
is invested in this tissue and becomes devascularized with this
dissection.141
A lateral neck dissection usually involves dissection of levels II,
III, and IV (see Fig. 68.3). This dissection puts the spinal accessory,
phrenic, vagus, cervical sensory, sympathetic trunk, hypoglossal, greater
auricular, and marginal mandibular branch of the facial nerves at
risk. The extent of node dissection should be guided by preoperative
1084 Part III: Specific Malignancies

and intraoperative ultrasound findings. Usually the great vessels can

be preserved, but more aggressive tumors can invade the internal Radioactive Iodine
jugular vein, and it should be sacrificed in this scenario. In addition, Remnant ablation with RAI is the standard adjuvant treatment for
to nerve injury, chyle leak is another complication of lateral neck selected patients with DTC. Because the primary goal of RAI is remnant
dissection.112,117 ablation, it can be administered only after a total or near-total thy-
roidectomy; otherwise the radioactive isotope will be absorbed by the
remnant thyroid and will not destroy any micrometastatic disease as
intended. In addition, RAI can be used as an adjuvant therapy after
total thyroidectomy to improve disease-free survival or as a therapeutic
modality to improve survival in patients with persistent disease.5 RAI
is administered 1 to 3 months postoperatively as iodine-131 (131I) as
sodium iodide in an oral form whose half-life is 7 to 8 days (Figs.
68.4 and 68.5). Consensus guidelines recommend a dose of 30 to
IIB 100 mCi for patients with low-risk tumors and higher doses
IB (100–200 mCi) for patients with residual disease, suspected microscopic
IA disease, or more aggressive histologic subtypes (i.e., tall cell, columnar
cell, or insular variants).5,147–149 To stimulate intracellular uptake of
IIA the isotope, the TSH concentration should be at least as high as
30 mU/L. There are two methods for achieving such an elevation in
TSH. The traditional method requires the patient to withdraw from
III thyroid hormone replacement over 4 to 6 weeks.2,150 A newer method
VA is to administer recombinant human thyroid-stimulating hormone
VI
(rhTSH). rhTSH is administered in the form of intramuscular injections
on 2 consecutive days followed by RAI on the third day. The advantage
of this method is that the patient does not experience an extended
IV period of hypothyroidism as with hormone withdrawal. However,
VB
long-term data on the effectiveness of rhTSH compared with traditional
withdrawal are lacking, although it appears effective for low-risk and
intermediate-risk patients; there is no available evidence to support
rhTSH use in patients with high risk of disease-related mortality and
VII morbidity.5 The US Food and Drug Administration (FDA) approved
rhTSH for thyroid remnant ablation in patients who do not have
evidence of metastatic disease.151,152 In addition to increasing the TSH
Figure 68.3  •  The central neck nodes (level VI) are usually the first nodes level, clinicians should also prepare patients by instructing them to
to receive drainage from the thyroid. follow a low-iodine diet for 1 to 2 weeks before RAI treatment. This

A B C
Figure 68.4  •  (A) Whole-body scan acquired 24 hours after administration of 2 mCi of iodine-123 (123I). (B) Spot view of the neck and chest. There are
several areas of uptake indicative of residual thyroid and functioning metastases in cervical lymph nodes. (C) Posttherapy scan made 7 days after administration
of 150 mCi of 123I. There is intense uptake in the region, but the resolution is not as good as with 123I. There is faint uptake in the liver on the posttreatment
scan as a result of metabolism of radioiodinated thyroid hormones at that site.

Figure 68.5  •  Positron emission tomography (PET) scan of a 75-year-old
woman with anaplastic cancer of the thyroid. Images were acquired 1 hour
after intravenous injection of 15 mCi fluorine-18 fluorodeoxyglucose (FDG).
There is intense uptake of FDG in the undifferentiated cancer.
diet requires patients to avoid foods that contain iodized salt, dairy
products, eggs, seafood, soybeans or soy-containing products, and
foods colored with red dye No. 3.148,149
Although some studies have shown no benefit to RAI therapy,153,154
other studies have demonstrated a reduction in locoregional recurrences
and distant metastases.69,131 As with the controversy over the extent
of thyroidectomy, the benefit of RAI for low-risk patients remains
unclear.150 The most recent ATA (2016) guidelines recommend remnant
ablation for all but the lowest-risk patients (unifocal, well-differentiated
tumor, <1 cm in size, confined to the thyroid gland without lymph
node metastases or multifocal papillary carcinoma with no other adverse
findings).5 These recommendations are supported by multiple systematic
reviews including one that was published in 2015.155–157 In these
low-risk patients, most of the available evidence suggests that RAI
does not improve disease-specific or disease-free survival.158–161 The
National Comprehensive Cancer Network (NCCN) guidelines require
a more thorough evaluation for the extent of remaining disease after
thyroidectomy, with a radioiodine scan 1 to 12 weeks postoperatively.
RAI ablation is not recommended if the stimulated Tg is less than
1 ng/mL and the radioiodine scan result is negative.147
Some studies have shown an increase in the risk of development
of secondary malignancies after RAI therapy. This has been examined
with use of the National Cancer Institute’s SEER database. Brown
and colleagues found that patients treated for DTC had significantly
higher rates of nonthyroid second primary malignancies than expected
in the general population. Although the excess risk was relatively
small, it was greater in the subset of patients who were treated with
RAI.162 Iyer and colleagues specifically examined low-risk patients
(T1N0) treated with RAI and found that their excess absolute risk
was 4.6 excess cases per 10,000 person-years at risk.163 As discussed
earlier, RAI clearly benefits patients with larger tumors and metastatic
disease, but the increased risk of secondary malignancies in low-risk
patients in whom the long-term benefit of RAI is questionable means
that careful patient selection for RAI treatment is necessary.
Hematologic malignancies are the most common secondary
malignancies after RAI, but there is also an association with kidney,
breast, bladder, skin, and salivary gland cancers.164–166 The more
commonly noted side effects after radioiodine treatment include dry
mouth, mouth pain, salivary gland swelling (sialadenitis), altered smell
and taste, conjunctivitis, and fatigue. Women should not be pregnant
at the time of treatment, nor should they become pregnant for at
Cancer of the Endocrine System  •  CHAPTER 68 1085
least 6 months after treatment. Similarly, men should avoid conception
for at least 6 months after treatment.149,156,166,167 Although a study has
shown that BRAF V600E mutations significantly reduce sodium-iodine
symporter expression and RAI uptake,168 there is no clear role of
molecular testing in guiding postoperative RAI.5,169
Thyroxine Suppression
Because all cells of follicular origin depend on TSH for growth, TSH
suppression through the administration of supraphysiologic doses of
levothyroxine (T4) remains an important strategy for maintaining
disease-free survival and overall survival.170 For high-risk patients
with incomplete resection, tumor invasion into adjacent structures,
or distant metastases, the physician should initially titrate T4 dosage
to a TSH level below 0.1 mU/L. Lower-risk patients should be treated
to achieve a TSH level at or slightly below the lower limit of normal
(0.1–0.5 mU/L).5,147 Once patients remain disease-free for at least 2
years, their TSH suppression can be liberalized to within the refer-
ence range. Patients with persistent disease should be kept at a TSH
level below 0.1 mU/L indefinitely. TSH suppression carries risks of
arrhythmias, anxiety, and osteoporosis. The risks and benefits should
be carefully considered, particularly in older patients. Because of the
risk of bone loss, the NCCN guidelines recommend daily calcium
and vitamin D supplementation for patients on TSH suppression.147
External Beam Radiation
Although 131I is the preferred adjuvant therapy for thyroid carcinoma,
external beam radiation sometimes plays a role in treating this disease.
Persistent, recurrent, anaplastic, or poorly differentiated tumors may fail
to take up 131I. Treatment of anaplastic thyroid tumors almost always
includes external beam radiation because these tumors often cannot
be completely resected and do not concentrate iodine. Although no
improvement in overall survival has ever been documented, external
beam radiation is often given after resection of poorly differentiated
tumors to reduce the risk of local relapse.171 The group at Memorial
Sloan Kettering Cancer Center has found that up to 85% of poorly dif-
ferentiated tumors display some iodine avidity, and therefore treatment
with RAI may remain worthwhile. Patients with incompletely resected
tumors, unresectable disease, and locoregional recurrence in a previously
operated field may benefit from external beam radiation.1,171,172
Chemotherapy
Because RAI often can be effective treatment for well-differentiated
tumors that have metastasized, cytotoxic chemotherapy has not been
extensively evaluated for metastatic thyroid cancers. For large burdens
of disease, anaplastic cancers, or poorly differentiated tumors that are
not iodine avid, chemotherapy becomes an important treatment
component after surgery or if the tumor is not resectable. In these
situations, chemotherapy confers minimal effects because these tumors
carry a very poor prognosis. Historically, doxorubicin was the most
effective single agent. Combination therapy with doxorubicin and
cisplatin resulted in modest objective response rates.173,174 Newer,
targeted therapies have shown some promise. Small-molecule tyrosine
kinase inhibitors (such as sorafenib or sunitinib) and antibodies
(anti–vascular endothelial growth factor [VEGF]) should be considered
in the context of ongoing clinical trials.147,175–177 Sorafenib and lenvatinib
have been approved for use in the United States for patients with
advanced RAI-refractory DTC. Although there was no improvement
in overall survival with sorafenib and lenvatinib, both were associated
with prolongation of progression-free survival (PFS) by 5 months.178,179
Recurrence
For most DTCs, the long-term survival rate exceeds 95%. Even
though disease-specific mortality rates remain quite low (<1%),
recurrence rates exceed mortality rates. For low-risk tumors, the
locoregional recurrence rates range from 2% to 10%180 and distant
recurrence rates are 1% to 2%.51,181 Higher-risk tumors (larger size,
1086 Part III: Specific Malignancies
extrathyroidal extension, cervical lymph node metastases) carry recur-
rence rates of 21% to 68%.62,180 For these reasons, a tailored approach
to follow-up and treatment of recurrent disease best serves patients
with DTC.
Surveillance
The original tumor characteristics and operative findings dictate the
follow-up schedule for DTC. Surveillance consists of measuring serum
Tg, TSH, and anti-Tg antibodies in addition to imaging. Cervical
ultrasound is a highly sensitive test for detection of metastatic
lymphadenopathy. Elevations in Tg in the absence of cervical disease
seen on ultrasound suggest distant metastases.5,56 Whole-body radio-
iodine scanning is sensitive for detecting iodine-avid bone or pulmonary
metastases.96,99 Poorly differentiated, aggressive tumors will not
concentrate iodine but can be detected with CT scan or FDG-PET
(see Fig. 68.5).83
The frequency of surveillance depends on the original tumor
characteristics and the AJCC stage.72 For lower-risk tumors, physical
examination, cervical ultrasound, and measurement of TSH, Tg, and
anti-Tg antibodies should be performed every 12 months. These studies
can be scheduled 3 to 6 months after the initial RAI treatment in
patients with high-risk tumors.5,147,177
Treatment of Recurrent Disease
Recurrence in the neck or cervical lymph nodes is best treated surgically.
The decision-making process of surgical resection should be based on
clinically apparent, macroscopic nodal disease confirmed with neck
ultrasound or CT scanning, rather than depending on Tg elevation
alone.143,182,183 Furthermore, small nodal recurrence (<8 mm in the
central neck or <10 mm in the lateral neck) can be managed with
active surveillance.182,184–186
Other treatment options such as percutaneous ethanol injection
(PEI) have shown some success in retrospective studies limited by
small sample sizes.187,188 External beam radiation should be considered
for recurrent disease that is unresectable or not iodine avid (Fig. 68.6).
Percutaneous ultrasound-guided laser ablation has shown promising
results for metastatic nodal disease.189 RAI cannot ablate bulky nodal
disease. After surgical resection, radioiodine can effectively ablate
micrometastatic disease throughout the body.
Medical treatment for recurrent or metastatic disease consists of
maintaining TSH suppression. Depending on the location of recurrence,
health of the patient, tumor risk stratification, and patient preference,
patients with metastatic disease can be referred for experimental
protocols using targeted therapies, can undergo traditional cytotoxic
chemotherapy, or can be treated with watchful waiting and supportive
TARGET
95%IDL
60%IDL
Figure 68.6  •  External beam radiation for thyroid carcinoma can be quite complex. On the left, the target for this bulky thyroid carcinoma is marked
with a dashed line. The high-dose volume (95% dose line) encompasses this target while avoiding the spinal cord. The radiosensitive spinal cord is in the
60% isodose line, which permits delivery of doses up to 70 Gy with this plan. On the right is a superimposition of the six cross-firing fields that are used to
create this dose distribution. The fields either avoid the spinal cord or include a lead block to shadow the spinal cord, protecting it from the high-dose radiation.
The treatment planning and dosimetry of thyroid carcinoma treatment is one of the most complex challenges in radiation oncology.
care.177 A multidisciplinary team experienced with metastatic thyroid
cancers best handles these decisions.
Medullary Thyroid Cancer
The prevalence of MTC has decreased from previously reported rates
of 5% to 10% of all thyroid cancers to 1% to 2%. This is because
of the increased incidence of PTC.190 Unlike DTC, MTC arises from
the parafollicular C cells instead of the follicular epithelium (see Fig.
68.1D). Hence, MTC is a neuroendocrine tumor (NET), and it shares
some properties common among neuroendocrine cancers, including
secretion of peptide hormones such as calcitonin, serotonin, or vasoac-
tive intestinal peptide (VIP). Most cases of MTC are sporadic, but
25% are a result of germline genetic mutations. Hereditary cases occur
either in isolation (familial medullary thyroid carcinoma [FMTC])
or as part of MEN syndrome type 2 (MEN2A or MEN2B).126,191
Diagnosis
Although any thyroid nodule could potentially harbor MTC, historical
features that may alert the physician to the potential for MTC include
a family history of MTC, PCC, hyperparathyroidism, or other mani-
festations of MEN2 syndromes.9 The median age of diagnosis is
approximately 50 years.192 In a SEER study that included 1252 patients
between 1973 and 2002, the authors found that 87% of the cohort
were white and 60% were female.192 As in evaluating all thyroid nodules,
neck ultrasound examination and FNA play a major role in diagnosing
MTC. In one retrospective study, ultrasound was found to be falsely
negative for ipsilateral and central node involvement in 17% and
14%, respectively, of patients with MTC with no ultrasound pathog-
nomonic features for MTC.193 Hereditary cases are often detected
through genetic screening to identify germline mutations in the RET
gene. Almost all sporadic cases manifest with a palpable neck mass,
which could be either the thyroid mass or a metastatic lymph node.
In contrast to sporadic disease, hereditary disease usually manifests as
multicentric and bilateral and involves the upper part of the thyroid.194,195
However, bilateral disease in sporadic MTC with negative RET
mutation can occur in up to 9% of patients.196–198 Lymph node
metastases occur in 35% to 50% of patients at initial diagnosis.199
Therefore, ultrasound evaluation of the central and lateral neck
compartments for suspicious lymph nodes becomes a crucial component
to the initial diagnosis.200
Because the parafollicular C cells are concentrated in the upper,
posterior portion of each thyroid lobe, many MTCs arise in a posterior
location, causing symptoms such as hoarseness or dysphagia as a result
of compression of local structures. If there is any concern for vocal

cord function, then direct laryngoscopy should be performed preop-
eratively.199 Markedly elevated calcitonin levels can cause symptoms
such as flushing, diarrhea, and weight loss.201 Distant metastasis to
the liver is the most frequent site.202 CT scan is a very sensitive imaging
modality for detection of local nodal and distant lung metastases.
Liver metastases are best detected with MRI, and routine use of
fluorine-18 fluorodeoxyglucose (18F-FDG) PET-CT is not recommended
in MTC evaluation because it is less sensitive.190,203
FNA sensitivity in detecting MTC ranges from 50% to 80% and
can be improved with the addition of immunohistochemical staining
of calcitonin.204,205 A meta-analysis of 15 publications showed an
accuracy of FNA of less than 50%.206 FNA characteristics of MTC
include the presence of stromal amyloid without thyroid follicles.
Because spindle-shaped cells may be seen, MTC can be mistaken for
parathyroid carcinoma or ATC unless the specimen is stained for
calcitonin, chromogranin A (CgA), or carcinoembryonic antigen
(CEA)—substances produced by MTC that confirm the diagnosis. A
more sensitive technique than immunohistochemistry on cytology
specimens is to measure the calcitonin level in the washout fluid from
an FNA.207 In addition, the presence of calcitonin messenger RNA
(mRNA) has been performed when the cytologic or histologic diagnosis
remains unclear.208
Several serum markers can confirm the diagnosis of MTC and are
useful in following patients for recurrence and metastases. Calcitonin
is commonly elevated in patients with MTC. Although a small percent-
age of normal patients will have some elevation in calcitonin, patients
with a diagnosis of MTC typically exhibit levels above 100 pg/mL.
In borderline cases, the diagnosis can be clarified by stimulating the
calcitonin with either intravenous calcium gluconate or pentagastrin.
Of note, calcitonin secreted by nonthyroid tissue such as lung cancer
or prostate cancer does not elevate with calcium gluconate or penta-
gastrin stimulation. Currently available immunochemiluminometric
assays (ICMAs) are more sensitive and specific for monometric calcitonin
and largely eliminate cross-reactivity with procalcitonin.190
Before the advent of genetic testing, these stimulated measure-
ments were used to screen patients at high risk for MTC.209 The
degree of calcitonin elevation correlates with tumor burden,
with nodal metastases found with basal calcitonin levels of 10 to
40 pg/mL and distant metastases found with calcitonin levels greater
than 150 pg/mL. Patients with calcitonin levels greater than 3000 pg/
mL are likely to have widely metastatic disease and are unlikely to
experience a cure.210
Preoperative measurement of serum CEA can also help risk-stratify
patients. Overall, CEA elevations occur in more than 50% of patients
with MTC, but a preoperative serum CEA level greater than 30 ng/mL
highly predicts the inability to cure the patient with surgery.211 CEA
levels above 100 ng/mL may signify extensive lymph node and distant
metastases. Following CEA levels postoperatively can also be used to
monitor disease progression. Simultaneous increases in CEA level
and calcitonin level indicate disease progression,190 whereas elevation
of CEA level in the presence of a stable calcitonin level is associated
with a worse prognosis because it may indicate tumor dedifferentiation
and distant metastases. However, normal CEA or calcitonin level
is rare and could represent an advanced dedifferentiated MTC or
misdiagnosis.190 Other markers, such as CgA and serotonin, may be
elevated in patients with MTC, as with many other NETs, but calcitonin
and CEA are the most useful for following MTC patients in the
long term.192,199,212
Genetic testing plays an important part in the initial management
because it can be used to identify familial disease and to risk-stratify
patients. Germline mutations in the RET gene characterize familial
disease.213 A small percentage of apparently “sporadic” disease will
also carry germline RET mutations, but truly sporadic cases frequently
harbor somatic RET mutations. For sporadic MTCs lacking RET
mutations, 18% to 80% have been found to have HRAS, KRAS, or
NRAS mutations.214–216 In sporadic MTC, presence of RET, especially
RET codon M918T, mutation usually predicts a poor prognosis.190,217,218
Cancer of the Endocrine System  •  CHAPTER 68 1087
Commercial testing is performed through polymerase chain reaction
(PCR) amplification of the patient’s germline DNA obtained from
the patient’s white blood cells. A spectrum of tumor aggressiveness
exists among the various RET mutations, and the timing of prophylactic
thyroidectomy is based on the specific mutation. Once a patient tests
positive for a germline RET mutation, the patient should be carefully
counseled regarding the risk to other family members and the patient’s
children. At-risk family members should be identified and also tested
so that prophylactic thyroidectomy can be offered at the appropriate
time. Although some overlap exists for genetic mutations associated
with MEN2A and familial MTC, distinct mutations are usually
associated with MEN2B.219,220
Treatment
Complete surgical excision is the treatment of choice for MTC. The
minimum extent of surgery for patients with clinically apparent disease
is a total thyroidectomy with bilateral central neck dissection. Eighty-one
percent of patients with palpable disease have central neck lymph
node metastases, and the addition of central neck dissection improves
cure rates over total thyroidectomy alone in patients with clinically
evident disease at presentation.221,222 The involvement of ipsilateral
and/or contralateral nodes has been found to be positively correlated
with presence and number of central nodes metastasis.223 Furthermore,
calcitonin level is helpful in preoperative risk assessment of nodal
disease. No risk of lymph node metastasis was found when serum
calcitonin level was less 20 pg/mL in a study of 300 patients with
MTC.224 In this study, metastasis to the ipsilateral central neck,
ipsilateral lateral neck, contralateral central neck, contralateral lateral
neck, and upper mediastinum were associated with calcitonin levels
greater than 20, 50, 200, and 500 pg/mL, respectively.224 The initial
approach to lateral neck lymph nodes continues to evolve. Historically,
the initial surgical treatment included an ipsilateral lateral compartment
neck dissection because up to 80% of patients will have ipsilateral
nodal metastases.196 However, current guidelines recommend performing
an ipsilateral lateral neck dissection if ultrasound or physical examination
detects lymphadenopathy in the lateral neck, if central compartment
lymph nodes are involved, or if the primary tumor is greater than
1 cm.200 Intraoperative assessment of nodal disease by surgeons has
sensitivity of 64% and specificity of 75%.221 Contralateral lateral neck
dissection is added when patients have bilateral tumors or there is
extensive lymph node disease on the ipsilateral side. Because some
patients require extensive neck dissection, these procedures are often
staged.199,200 Unlike DTC, in which micrometastatic disease can be
effectively treated with RAI ablation, the only effective treatment for
MTC is complete surgical resection. Therefore all evident disease must
be resected for the best chance of long-term cure. According to the
revised ATA guidelines, complete thyroidectomy is not indicated unless
the patient has a RET germline mutation, elevation of serum calcitonin
level, or evidence of residual MTC on images.190
Prophylactic thyroidectomy is recommended for at-risk family
members in hereditary MTC. Current recommendations for the timing
of prophylactic thyroidectomy balance the need to remove the at-risk
organ before it develops clinically apparent disease with the risks of
surgery. In hereditary MTC, an age-related progression exists from
C-cell hyperplasia to carcinoma, and, ultimately, nodal metastases.
The optimal timing of prophylactic thyroidectomy depends on the
risk level of the RET mutation. In general, current guidelines recom-
mend operating on children with MEN2A and familial MTC by age
5 years, whereas those with MEN2B should be operated on before 6
months of age.225 Prophylactic surgery should consist of at least a total
thyroidectomy. The role of prophylactic lymph node dissection in
familial disease remains controversial. Lymph node metastases are
present in 6% of screened patients,226 and therefore some argue that
prophylactic central lymph node dissection should be performed.
Opponents to this approach state that with normal preoperative
ultrasound findings, normal calcitonin level (basal and/or stimulated),
and a normal CEA level, the risk of occult nodal disease is very low
1088 Part III: Specific Malignancies
and does not outweigh the risks of a central neck dissection such as
permanent hypoparathyroidism.9,221,226 Because any complications
resulting from prophylactic surgery become lifelong problems for the
patient, experienced surgeons should perform prophylactic surgery.
Before proceeding with surgery, the surgeon should screen patients
with hereditary disease for associated conditions such as PCC (MEN2A
and MEN2B) and hyperparathyroidism (MEN2A).220,226
All patients will require thyroid hormone replacement once the
thyroid is removed, but TSH suppression is not required. After surgery,
the next phase of treatment is surveillance. This begins 2 to 3 months
postoperatively with a new baseline calcitonin and CEA measurement.
If the calcitonin is undetectable, these patients can be followed with
yearly calcitonin measurements. Imaging is undertaken when the
calcitonin level rises.
A spectrum of disease severity exists for both hereditary and sporadic
MTC, and therefore the natural history of MTC varies widely. Distant
metastases in the lung, liver, or bone can arise and lead to death quite
quickly. On the other hand, many patients live with a large tumor
burden and very high calcitonin levels with few symptoms. Others
develop intractable diarrhea. In this case, cytoreductive surgery227 or
somatostatin analogues such as octreotide can palliate severe symp-
toms.227 Overall 10-year survival rates have been reported as 75% and
95% for tumor confined to the thyroid and regional stage disease,
respectively, in a SEER registry study.192 In this study, age and stage
were found to be stronger predictors of survival in univariate analysis.192
Furthermore, calcitonin doubling times of less than 6 months indicate
worse prognosis, with 5-year and 10-year survival rates of 25% and
8%, respectively.228 Conventional chemotherapy regimens with
doxorubicin, dacarbazine, capecitabine, and 5-fluorouracil (5-FU) have
demonstrated limited efficacy in patients with MTC. According to
the revised ATA guidelines, systematic chemotherapy should not be
used as a first-line treatment.190 Newer, targeted therapies block the
RET receptor tyrosine kinase or its multiple downstream pathways,
such as the extracellular signal-related kinase (ERK), phosphatidylino-
sitol 3-kinase (PI3-K)/Akt, p38 mitogen-activated protein kinase
(MAPK), and c-Jun N-terminal kinase pathways.106,199,229 Some of
these tyrosine kinase inhibitors inhibit multiple signaling pathways
simultaneously.106,230 These targeted therapies have been evaluated in
multicenter trials.230,231
The FDA has approved one of these targeted therapies, vandetanib,
for treatment of metastatic MTC. Vandetanib is a small-molecule
inhibitor of the VEGF receptor, epidermal growth factor (EGF) receptor,
and the RET tyrosine kinase.232 In a randomized controlled clinical
trial, patients treated with vandetanib experienced a median PFS of
22.6 months compared with 16.4 months in patients treated with
placebo.230 Another FDA-approved tyrosine kinase inhibitor is
cabozantinib, which targets VEGFR1 and VEGFR2, c-MET, and
RET. In a phase I/II trail of 35 patients with MTC, 17 patients had
a partial response.233 Patients on tyrosine kinase inhibitors should be
monitored for hypothyroidism.190 Important to note, none of these
agents have been shown to prolong overall survival. More research is
currently being conducted on other potential therapies.
ADRENOCORTICAL CANCER
Incidence
Adrenocortical cancer (ACC) is a rare endocrine malignancy with an
incidence of 1 to 2 per million people; it causes less than 0.2% of all
cancer deaths.234,235 After ATC, ACC is the second most aggressive
endocrine cancer. Although ACC can develop at any age, it occurs in
a bimodal age distribution: in patients younger than 5 years, and those
in the fourth and fifth decades of life.236 In general, ACC in adults
is more aggressive than in children, with rapid disease progression.
Women are affected more than men, at a ratio of 1.5 : 1, and are
more likely to have a functional tumor.237 The incidence of ACC
also varies among countries. The highest incidence is in southern
Brazil, with a 10 to 15 times higher incidence in children and with
the majority of sporadic ACCs possessing a germline TP53 (R227H)
mutation.238–240
Pathogenesis
Most ACCs arise sporadically, and the pathogenesis is not completely
understood. It is not known if ACC develops from hyperplastic or
adenomatous adrenal nodules. However, several genetic alterations
have been identified; the most common mutation involves overexpres-
sion of the insulin-like growth factor (IGF) gene. Next-generation
sequencing in 1051 children with cancers revealed that 27 (69%) out
of 39 patients with ACCs possessed a TP53 mutation.241 In this study,
family history was not a predictor of an underlying predisposition
syndrome in most patients.241 β-Catenin CTNNB1 was associated
with poor outcome and decrease in overall and disease-free survival
in patients with ACCs.242 Another potential tumor suppressor gene,
ZNRF3, was identified in 21% of patients with ACCs with use of
exome sequencing and single-nucleotide polymorphism (SNP) array
analysis.243 Furthermore, tumors containing hypermethylated DNA
have also been found to be associated with a poor prognosis.244 Other
growth factor and growth factor receptor mutations have also been
identified in sporadic ACC.235,245 Familial tumor syndromes that involve
ACC include MEN1 (11q13), Li-Fraumeni syndrome (17p13),
Beckwith-Wiedemann syndrome (11p15.5 and 15q11–13), and Carney
complex (17q23–24 or 2p16).235,246,247
Clinical Presentation
Most ACC patients are asymptomatic until the tumor reaches a size
that causes compression of nearby structures, local invasion, or distant
metastasis. Although symptoms are vague, they can include fever,
early satiety, weight loss, pain, anemia, nausea, and fatigue. The presence
of these symptoms in the setting of ACC is ominous. The mean
duration from the onset of symptoms to the diagnosis of ACC varies
from 6 to 16 months and appears to be independent of whether the
tumor is functional.234–236
In 40% to 60% of the patients, ACC results in increased hormone
production (functional) that may cause symptoms and assist in cor-
rectly diagnosing these aggressive tumors. Because most ACCs are
inefficient in mature steroidogenesis, they can secrete a variety of
steroid precursors that result in clinical or subclinical syndromes. As
many as 75% of the ACCs are associated with subclinical Cushing
syndrome, which can be diagnosed with biochemical testing.245,248
Clinical Cushing syndrome with the classic symptoms may be present
in up to 50% of the patients with functional ACC. Virilization caused
by excessive androgen steroids or androgenic precursors is identified
in approximately 20% of the patients, and the combination of clinical
Cushing syndrome and virilization is present in 10% of the functional
ACCs. Cushing syndrome with virilization almost always indicates
ACC. Other clinical manifestations include feminization (5%–8%),
hypoglycemia (<5%), and hypokalemic alkalosis (<5%).235,249 Men may
have gynecomastia or low libido owing to estrogen overproduction by
ACC.250 Eighty percent of children have virilization; 6% have isolated
glucocorticoid excess.239,251
Metastases are present in 20% to 50% of the patients with ACC
at the time of diagnosis, with lungs (40%–50%), liver (40%), and
lymph nodes (20%–30%) being the most common sites. Less common
sites include the bones, spleen, pancreas, and diaphragm.235,249,252
Diagnosis
The correct diagnosis of ACC is important for appropriate management;
however, preoperative diagnosis of ACC is complex. At present, the
diagnosis relies on clinical assessment, urinary and plasma biochemical
tests, and imaging studies. Clinical suspicion should be raised in any
patient with adrenal Cushing syndrome with an adrenal mass, increased

urinary 17-ketosteroids, and age younger than 20 years, or in patients
with an adrenal mass, increased urinary 17-ketosteroids, virilization
or feminization, weight loss, anemia, or fever.235,249
Hormonal workup includes plasma adrenocorticotropic hormone,
cortisol, and urinary 17-ketosteroids, with or without a dexamethasone
suppression test. Adrenal incidentalomas should also be evaluated
with plasma or urinary metanephrines to rule out PCC, and with
renin and aldosterone levels in patients with hypertension to rule out
aldosteronoma.253
The role of imaging in the evaluation of adrenal mass is valuable
for assessing the tumor size and other specific imaging characteristics.
It has been demonstrated that 92% of the ACCs are larger than
6 cm254 and that the risk of malignancy increases with adrenal tumor
size as follows: 2% for tumors smaller than 4 cm, 6% for tumors that
are 4 to 6 cm, and 25% for tumors larger than 6 cm.248,255 Furthermore,
adrenal masses that increase in size within a 6-month period are also
suggestive of malignancy.235 CT is the most useful imaging study to
evaluate adrenal tumor size, adjacent organ involvement, and resect-
ability. Irregular borders, heterogeneity, calcifications, radiodensity
greater than 25 Hounsfield units (HU), delayed washout of less than
50%, and extension to the inferior vena cava all suggest malignancy.
In the largest reported series evaluating CT imaging for ACC, the
authors found that improved diagnostic accuracy could be obtained
by selecting a radiodensity cutoff for adrenal lesions of 13.9 HU at
CT imaging. Sensitivity was 100% and specificity was 68%.256 In
addition, when performed correctly, intravenously administered contrast
material washout of less than 50% carries a sensitivity and specificity
of 100%.235,249,253,257 With gadolinium-enhanced magnetic resonance
imaging (MRI), malignant lesions show rapid and marked enhancement
and a slower washout pattern on T2-weighted images. Other suspicious
features at MRI include peripheral enhancement, central necrosis,
and internal hemorrhage. The overall MRI sensitivity and specificity
are 81% to 89% and 92% to 99%, respectively.258
Two other imaging modalities show encouraging results. The
sensitivity of FDG-PET was reported to be 97% after a systematic
review that included 21 studies for identifying ACC, with no difference
reported between FDG-PET and FDG-PET/CT.259 C-metomidate-PET
(MTO-PET) is another emerging adrenal imaging technique with
similar accuracy.260,261 Another imaging technique is (123I)iodometomi-
date (IMTO) scanning, which has the ability to reveal adrenal lesions
with a sensitivity and a specificity of 89% to 85% and 38% to 100%,
respectively.262,263
FNA is a tool that should be discouraged for the diagnosis of ACC
because it has a high false-negative rate and it cannot accurately
distinguish a benign from a malignant adrenal mass.235,253,264 The
definitive diagnosis of ACC is through pathologic evaluation. Grossly,
these are large tumors that may invade the adjacent organs and large
blood vessels, such as the inferior vena cava. The tumors are yellow
to tan, with areas of necrosis and hemorrhage. In the absence of
metastatic disease or local, capsular, or vascular invasion, the diagnosis
of malignancy may be difficult. The Weiss criteria incorporate nine
histologic features that help distinguish between malignant and benign
tumors. These features include high nuclear grade (III or IV), mitotic
rate greater than 5 per 50 high-power fields (HPFs), atypical mitoses,
diffuse architecture, microscopic necrosis, 25% or fewer clear cells,
capsular invasion, sinusoidal invasion, and venous invasion. A tumor
with a score of 2 or lower is classified as benign, whereas a tumor
with a score 3 or greater is considered malignant. Evaluation of
molecular markers such as microRNAs, IGF2 overexpression, increased
Ki-67, and specific genetic variations may prove to be a more accurate
diagnostic tool.236,245,248,264 Ki-67 tumor expression greater than 10%
positively correlates with a worse prognosis.265
Treatment
The management of ACC should involve a multidisciplinary approach
and is tailored to each patient’s disease status.
Cancer of the Endocrine System  •  CHAPTER 68 1089
Primary Disease
Surgery
Surgical resection of the primary tumor is the only means to achieve
cure, and every attempt must be made to identify the patients who
are candidates for curative resection.235,248,252 Patients with known or
suspected ACC should be referred to highly experienced surgeons.
The surgeon can evaluate the size and local invasiveness of the tumor
and decide on the approach and extent of surgery. Complete hormonal
assessment should be obtained before surgery in order to determine
the functional status of the adrenal lesion. Tumors that are localized
to the adrenal gland should be resected with adequate margins. Resection
can be performed via an open (anterior or posterior) or a laparoscopic
approach. Although the role of laparoscopy for the resection of ACC
is controversial, surgeons are expanding the indications for laparoscopy
for localized tumors with comparable outcomes.266 At present there
are no randomized controlled trials that evaluate the role of laparoscopic
surgery for ACC.
Before incision, patients should be given a stress dose of steroids
because the contralateral gland may be suppressed.235 At surgery, every
attempt must be made to achieve clear surgical margins, and, in cases
of locally advanced disease, en bloc resection of involved organs should
be performed. Tumor spillage and incomplete resection are associated
with a poor prognosis.267 Regional lymph node dissection should be
performed for involved lymph nodes, and such involvement should
be assessed in every patient with known ACC.
Advanced ACCs may involve the kidney, pancreas, spleen, liver,
diaphragm, renal vein, and inferior vena cava. Tumors may even
extend through the inferior vena cava to the right atrium and the
superior vena cava. For such advanced tumors, multidisciplinary teams
are of the utmost importance, because cardiopulmonary bypass or
hypothermic circulatory arrest is often required.234,248,249 Table 68.6
outlines the staging of ACC. There is no consensus yet about routine
lymphadenectomy for patients with ACCs. A study of 283 patients
with completely resected ACCs found reduced risk of recurrence
and disease-related death among patients who underwent routine
lymphadenectomy.268
Postoperative surveillance should be continued for many years
because recurrences have been documented as long as 12 years after
resection. For patients with elevated dehydroepiandrosterone sulfate
(DHEAS) at presentation, the postoperative levels may be used for
Table 68.6  Adrenocortical Cancer Staging
TNM
T T1 Size ≤5 cm, no local invasion
T2 Size >5 cm, no local invasion
T3 Presence of local invasion without involvement of
adjacent organs
T4 Invasion of adjacent organs
N N0 No positive lymph nodes
N1 Positive lymph nodes
M M0 No distant metastases
M1 Distant metastases
STAGING
I T1, N0, M0
II T2, N0, M0
III T3, N0, M0
T1-2, N1, M0
IV T4, N0, M0
T3, N1, M0
T1–4, N0–1, M1
1090 Part III: Specific Malignancies
surveillance. Patients with nonfunctional tumors should be evaluated
at regular intervals with physical examination and CT scan.234,235,249
Mitotane
Mitotane (o,p′-DDD or 1,1-dichloro-2[o-chlorophenyl]-2-[p-
chlorophenyl]ethane) is a pesticide isomer that is directly toxic to
adrenocortical cells. Its exact mechanism is yet to be elucidated; however,
it leads to mitochondrial disruption and adrenocortical cell necro-
sis.235,248 An inhibitory effect of mitotane of sterol-O-acyl-transferase
1 (SOAT1) that leads to accumulation of toxic lipids has been identified
as one of the mechanisms of action of mitotane on ACCs.269 Although
the first use in humans was described in 1959, there are no randomized
controlled trials that have shown benefit with mitotane treatment
over controls. Retrospective studies found that mitotane improves
recurrence-free survival in the adjuvant setting. Recurrence rate in
patients treated with mitotane was 49% to 55% as compared with
70% to 90% in the control groups.270,271 The effect of mitotane alone
on disease-free survival has yet to be established. An ongoing prospective
randomized study in Europe will evaluate the efficacy of adjuvant
mitotane therapy in patients with low to moderate recurrence risk.
Most patients are started at a low dose of 0.5 g twice per day and
increased to 6 g/day over 4 to 12 weeks as tolerated; the therapeutic
window of mitotane is narrow, and toxicity may be evident when
doses reach 8 to 10 g/day. Side effects of mitotane are predominantly
gastrointestinal (GI), neurologic, and cutaneous. GI side effects occur
in approximately 80% of patients and include anorexia, nausea and
vomiting, and diarrhea. Neuromuscular toxicity occurs in 4% to 60%
of patients, and the common symptoms are lethargy and somnolence.
Vertigo is observed in 15% of the patients. Leukopenia and liver
toxicity are less common.272,273 These side effects are often severe enough
to require discontinuation of treatment. Tumor regression occurs in
approximately 25% of patients, and it is rarely apparent before 6
weeks of treatment.274
Chemotherapy
The role of chemotherapy for the management of ACC remains under
investigation. As many as 20% of ACC patients have unresectable
tumors at presentation, and the prognosis of such patients is dismal.
Mitotane alone or with the combination of chemotherapy remains
the standard treatment for unresectable or metastatic disease. A recent
randomized controlled study compared 149 patients treated with
mitotane and streptozocin (M-SZ) with 148 patients treated with
mitotane, etoposide, doxorubicin, and cisplatin (M-EDP). Patients
in the M-EDP group had a significantly higher response rate than
those in the M-SZ group (23% versus 9%) and longer median PFS
(5 versus 2 months). There was no significant difference in overall
survival (15 versus 12 months).275
Radiotherapy
Radiotherapy to the tumor bed has also been used as adjuvant treatment
after ACC resection. A small retrospective study (n = 14 in each arm)
identified a local recurrence reduction from 79% to 19% with adjuvant
radiotherapy.276 Local control was observed in 56% to 100% of patients
treated with adjuvant radiotherapy in several studies.276–280 However,
this has not translated to improved survival. At present there are no
clear recommendations for radiation therapy for ACC regarding patient
selection, indications, or dosage.281
Hormonal control
Of patients with a heavy tumor burden, 40% to 60% have symptoms
associated with excessive hormonal secretion.252,282 Several different drugs
may alleviate these symptoms. As mentioned earlier, mitotane is toxic to
adrenocortical cells. Ketoconazole inhibits steroid synthesis via inhibi-
tion of C17-20 desmolase. Ketoconazole toxicity includes many side
effects, and because it inhibits cytochrome P450, it may interfere with
doxorubicin and etoposide. Metyrapone reduces cortisol and aldosterone
production via inhibition of cortical 11β-hydroxylation. Toxicity is
more tolerable than with ketoconazole, and metyrapone is also a
cytochrome P450 inhibitor. Etomidate also inhibits 11β-hydroxylase
and cholesterol side-chain cleavage and thus reduces cortisol and
aldosterone synthesis.235 The role of IGF2 in the progression of ACC
and its overexpression by ACCs has been clearly defined. Therefore,
therapeutic agents targeting IGF2 have been developed. In a phase
II trial, linsitinib, an inhibitor of the IGF1 receptor (IGF1R) and
the insulin receptor, did not increase overall survival in patients with
ACCs and therefore was not recommended as a treatment option.283
Recurrent or Metastatic Disease
As many as 20% to 50% of patients with ACC have metastatic disease
at initial presentation; 50% to 90% of patients will experience recurrence
after surgical resection.232,248,249 Patients who have resectable recurrent
or metastatic disease should be referred to highly experienced centers
for excision because limited disease burden can be resected with
acceptable morbidity. Patients undergoing complete resection for
recurrent or metastatic disease have a significantly improved median
survival of 74 months, compared with 16 months for those with
incomplete resection.284 Patients with unresectable recurrent or meta-
static disease should be treated with mitotane alone or combination
chemotherapy even though the effect on overall survival is not proven.235
Prognosis
ACC carries a poor prognosis, with a median survival of 38 months
and an overall 5-year survival rate of less than 40%.234,235,249 Prognosis
mainly depends on the tumor stage at presentation and varies dramati-
cally among studies. Table 68.7 summarizes the median survival and
5-year survival rates for the different stages.234,235,248 A better prognosis
has been observed in patients with stage II ACC who received adjuvant
mitotane.285 Multiple variables have been shown to portend poorer
outcome, including tumor size over 12 cm, age older than 55 years,
nodal or distant metastases at time of initial presentation, adjacent
organ invasion, poorly differentiated histologic features, high mitotic
rate, atypical mitoses, and tumor necrosis.236,238
MALIGNANT PHEOCHROMOCYTOMA
Incidence
PCCs are rare adrenal tumors that secrete catecholamine and are
derived from the chromaffin cells of the adrenal medulla. Paragangliomas
are similar tumors that are located at extraadrenal sites along the
sympathetic chain (organ of Zuckerkandl, pelvis, abdomen, media-
stinum, and neck).286,287 The estimated prevalence of PCC is 1 : 2500
to 1 : 6500 in Western countries, with an incidence of 2 to 8 per 1
million adults. The gender distribution of PCC is nearly equal, and
the peak age of occurrence is the third to fifth decades of life; however,
familial PCC occurs at an earlier age.286–288
The rate of malignancy differs between PCC and extraadrenal
paragangliomas. Although only 3% to 13% of the PCCs are malig-
nant, the estimated rate for paragangliomas is 15% to 35%.287,289
Some studies have suggested that the rate of malignancy increases
with older patient age and larger tumors. Specific mutations in the
Table 68.7  Median and 5-Year Survival
Adrenocortical Cancer Stages
Median Survival (months) 5-Year Survival
Stage I 61–110 62%–92%
Stage II 23–98 58%–87%
Stage III 7–17 18%–40%
Stage IV <12 0%–14%

succinyl dehydrogenase (SDH) gene family (SDHB) are associated
with a higher rate of extraadrenal tumors, and the malignancy rate
approaches 50%.287,290
Pathogenesis
Most PCCs are sporadic tumors; however, up to 24% develop from
hereditary germline mutations. Ten percent of PCCs are associated with
MEN2A or MEN2B with a mutation in the RET gene (10q11.2), and
these are more frequently bilateral with a low (3%) malignancy rate.
A mutation in the von Hippel-Lindau gene (3p25-26) is associated
with 5% malignancy rate. PCC may be a part of neurofibromatosis
(NF) type 1 with a mutation in NF1 gene (17q11.2). The malignancy
rate in these patients is 11%. The aforementioned SDH gene family
differs in malignancy rates. Mutation in the SDHB gene (1q36.13)
is associated with a 50% to 66% malignancy rate, and mutation in
SDHD gene (11q23) is associated with less than 3% malignancy.287,291,292
Clinical Presentation
Malignant PCCs are histologically and biochemically similar to benign
ones. Metastatic spread is the only true indicator of malignant behavior
according to 2004 World Health Organization (WHO) criteria.293
More than 50% of malignant PCCs may be nonfunctional, and their
diagnosis is made only after resection and pathologic evaluation.
Functioning malignant PCCs manifest with the same secretory pattern
as benign tumors. The classic triad of symptoms in patients with PCC
includes episodes of headache, tachycardia, and sweating. Most of the
patients with PCC do not have all three classic symptoms. Paroxysmal
hypertension may be observed in nearly 50% of the patients.294,295
Other signs and symptoms include papilledema, weight loss, polyuria,
polydipsia, orthostatic hypotension, hyperglycemia, leukocytosis,
increased erythrocyte sedimentation rate, constipation, and psychiatric
disorders.296–298 Cardiomyopathy and pulmonary edema may be caused
by the catecholamine excess.299 Symptoms and signs may be exacerbated
or triggered by stress or consumption of tyramine.296,298 As many as
50% of patients with MEN2 are asymptomatic at presentation, and
a similar finding has been observed with PCC associated with von
Hippel-Lindau disease, in which 35% of these patients lack symptoms.
This low rate of symptomatic patients may be a result of early detection
by screening of at-risk patients.300,301
PCC should be suspected in patients who have one or more of
the following:
• Classic triad spells
• Self-limited palpitations, tremor, or pallor
• Hypertension resistant to medical treatment or onset before age
20 years, with or without atypical diabetes mellitus
• Hypertensive response to stress (surgery, anesthesia, other procedure)
• Presence of other syndrome-associated disease in patient of family
member
• MEN2—MTC, primary hyperparathyroidism, mucosal neuromas;
marfanoid habitus
• von Hippel-Lindau—angiomatosis, hemangioblastomas, pancreatic
cysts, café au lait spots, renal cell carcinoma
• NF1—neurofibromas, café au lait macules, freckles, optic glioma,
Lisch nodules, osseous lesions
• SDH—renal cell carcinoma, GI stromal tumors, testicular seminoma
• Carney syndrome—pulmonary chondromas and gastric stromal
tumor
• Idiopathic dilated cardiomyopathy
• Incidental adrenal mass
Diagnosis
The diagnosis of PCC is confirmed with the measurement of urinary
or plasma fractionated metanephrines and catecholamines, which is
Cancer of the Endocrine System  •  CHAPTER 68 1091
highly accurate for functional PCCs. The sensitivity and specificity
of each test vary among institutions. It has been suggested that measure-
ment of plasma fractionated metanephrines is the superior test.286,298,302
Other biochemical diagnostic tests include clonidine suppression test,
plasma catecholamines, CgA, neuropeptide Y, vanillylmandelic acid,
and provocative testing; however, because of variable accuracy, these
tests have not gained wide acceptance.286,298,302 To overcome the problems
with fluorometric analysis, most laboratories now measure fractionated
catecholamines and fractionated metanephrines.303
Imaging studies to localize the tumor should follow biochemical
diagnostic confirmation. Approximately 90% of the tumors are PCCs
within the adrenal and 95% of the tumors are within the abdomen. Both
CT and MRI are highly sensitive (97% to 100%), but the specificity is
only 60% to 75%. For malignant PCC, these imaging modalities may
identify local invasion or, occasionally, distant metastases.288,298,302,304
123
I-metaiodobenzylguanidine (123I-MIBG) is a compound resem-
bling norepinephrine that is taken up by adrenergic tissue. It is highly
specific (>96%) and may be used when CT or MRI findings are
negative or to identify extraadrenal metastases when malignancy is
suspected.305 OctreoScan and FDG-PET constitute the third-line
imaging modalities and are of benefit when malignancy is suspected.
PET with 6-(18F)-fluorodopamine ([18F]-DOPA) can be used to detect
extraadrenal PCCs and neck paragangliomas; however, this imaging
modality is not yet available at all centers.302,304
Although the risk of malignancy increases with size for all PCCs,
size alone is not a reliable predictor of malignancy in local disease.
Because pleomorphism, nuclear atypia, abundant mitotic figures, and
even capsular invasion may be observed in benign PCCs, the diagnosis
of malignancy may be difficult at pathologic assessment. Several other
methods have been evaluated to differentiate between benign and
malignant PCC. CgA has been shown to be significantly increased
in malignant tumors. Several genetic markers such as SDHB, MIB-1,
nm23-H1, tissue inhibitor of metalloproteinase-4 (TIMP-4), BRMS-1,
TXNIP, CRSP-3, and E-cadherin (E-cad) are also dysregulated in
malignant PCC. Tissue markers such as cyclooxygenase-2, secretogranin
II-derived peptide, heat shock protein 90, hTERT, and Ki-67 have
all been evaluated with encouraging results.286,287,306 Thompson created
a PCC of the adrenal gland scaled score (PASS) based on histologic
features. The following items and their values (in parentheses) were
given to each tumor. Together, if present, these features would determine
the PASS: large nests or diffuse growth greater than 10% (2), central
or confluent tumor necrosis (2), high cellularity (2), cellular monotony
(2), tumor cell spindling (2), more than 10-HPF mitotic figures (2),
atypical mitotic figures (2), extension into adipose tissue (2), vascular
invasion (1), capsular invasion (1), profound nuclear pleomorphism
(1), and nuclear hyperchromasia (1). The PASS was later validated
in another cohort, and it was identified that all cases with a PASS of
less than 4 were benign, whereas all malignant cases had a PASS
greater than 6.307,308
Treatment
The management approach to malignant PCCs generally follows the
algorithm for ACC.
Surgery
Surgery should be offered to all patients with PCC unless the tumor
is deemed unresectable. At surgery, every attempt must be made to
resect the entire adrenal gland with clear margins. Surgical debulking
is considered the mainstay of therapy even for metastatic PCCs, with
the rationale of reducing the circulating catecholamine levels and to
increasing the uptake of future 131I-MIBG treatment.286,289,297,304
Preoperative treatment should include fluid hydration to increase
intravascular volume and α- blockade to control hypertension. This
treatment should be initiated 10 to 14 days before surgery and to
the point of mild orthostatism; β-blockade may be added in patients
with tachycardia.
1092 Part III: Specific Malignancies
Adrenalectomy should be performed in patients with PCC, and
extraadrenal resection should be offered to patients with paragangliomas.
The transabdominal laparoscopic approach is the most commonly
used, and posterior retroperitoneal surgery may be performed for
smaller bilateral tumors. Highly experienced surgeons may perform
laparoscopy, and it can be safely completed even for tumors larger
than 6 cm.309 A low threshold for open surgery should be practiced
for locally advanced tumors and paragangliomas in complex loca-
tions.294,310 Minimally invasive robotic adrenalectomy has been used
with comparable outcomes to laparoscopy. Surgical survival rates are
98% to 100%; however, the morbidity associated with surgery is more
common, and adverse perioperative complications occur in 23% to
37% of the patients.289,309,311,312
Laparoscopic transabdominal adrenalectomy begins with placement
of the patient in a lateral decubitus position. Pneumoperitoneum is
established to a pressure of 15 mm Hg, and three or four trocars are
introduced into the subcostal space, from the midclavicular line to
the posterior axillary line.
For tumors located on the right side, the liver is first mobilized to
facilitate exposure of the adrenal gland and the adrenal vein. The
dissection of the posterior peritoneum begins superiorly and along
the medial border of the adrenal gland. The inferior vena cava is
identified and the lateral border is dissected to identify the short right
adrenal vein entering the inferior vena cava. Once the adrenal vein
has been identified, the anesthesiologist should be notified before it
is divided because this may result in hypotension. The remaining
retroperitoneal attachments are dissected with ultrasonic shears. The
adrenal gland with the tumor is then removed via an endoscopic bag
through the 10-mm port, and the tumor is examined on the back
table to ensure complete excision.
Laparoscopic left adrenalectomy follows the same access approach,
but on the left side. On this side, the spleen is mobilized so that the
spleen and the distal pancreas fall medially to facilitate exposure of
the adrenal gland. Sometimes the splenic flexure of the colon also
requires mobilization to expose the adrenal gland. A relatively avascular
plane between the pancreas and adrenal gland is dissected, and the
borders of the adrenal gland are identified. The left renal vein drains
into the renal vein. This vein is carefully dissected and divided. The
remainder of the gland is dissected free from the surface of the kidney
with ultrasonic shears as on the right side.
Resectable recurrent disease or isolated metastases are optimally
treated with surgical resection or debulking of tumor burden, especially
if the patient is symptomatic.286,304
131
I-MIBG
MIBG is structurally similar to noradrenaline and is thus concentrated
into chromaffin cells. MIBG may be used for imaging, and the addition
of RAI–labeled MIBG can be an effective therapeutic option. This
mode of therapy is completely useless in malignant PCCs that do not
take up MIBG. Important to note, external beam radiation abolishes
the ability of malignant PCC to take up MIBG, and therefore patients
who have been treated with external beam radiation cannot be treated
with MIBG. Tumor response after 131I-MIBG treatment is 30% to
67% and biochemical response is 45% to 67%. Symptomatic relief
may be achieved in 76% to 89% of treated patients. 131I-MIBG
treatment can be repeated at 6-month intervals.313 The effect of
131
I-MIBG on survival is not clearly established because it is clearly
not curative. Its high side effect profile, mainly myeloablative effects,
makes it less than ideal, but it still remains the first line of adjuvant
therapy.286,287,289 However, treatment with 131I-MIBG in patients with
malignant PCC that take up MIBG has been shown to be effective
in alleviating symptoms by suppressing catecholamine secretion in
metastatic tumors.313,314
Chemotherapy
Systemic chemotherapy should be reserved for patients with unresect-
able, metastatic, or rapidly progressing malignant PCC. In 1988, 18
patients with malignant PCC were treated at the National Institutes
of Health (NIH) with combined cyclophosphamide, vincristine, and
dacarbazine (CVD therapy). In a 22-year follow-up, the tumor response
rate was 55% and the biochemical response was 72%. Patients who
are candidates for CVD therapy should be started on α-blockade,
because the treatment causes catecholamine release. Because CVD
therapy has no proven survival benefit, it is reserved for patients who
were unresponsive to 131I-MIBG or symptomatic patients with unresect-
able disease.286,287,315 A systematic review and meta-analysis of four
studies that evaluated patients treated with CVD for malignant PCCs
and paraganglioma suggested that a partial response on tumor volume
can be achieved in 37% of patients and catecholamine suppression
can be achieved in 40% of patients.316
Radiotherapy
Malignant PCC is considered a radioresistant tumor; however, the
main benefit of radiation therapy is to control pain and symptoms
associated with bone and lymph node metastases. CyberKnife radiation
and radiofrequency ablation are the most commonly used methods
for bone metastases, but more studies are needed to determine their
efficacy in malignant PCC.287,317
Radiolabeled somatostatin analogue (DOTA-Tyr[3])-octreotide
(DOTATOC) has shown some response with no major adverse events.
It may be used in patients with somatostatin receptor–positive PCC.318
Hormonal Control
Patients with unresectable, recurrent, and metastatic disease may have
severe effects from the excessive catecholamine secretion. These patients
have several treatment options. Phenoxybenzamine is an irreversible,
long-acting, nonselective, α-adrenergic receptor blocker that is mostly
used for preoperative preparation of these patients, but it can also be
used for symptom control. Nicardipine is a long-acting calcium channel
blocker that blocks the transport of norepinephrine-mediated calcium
into vascular smooth muscle. Metyrosine inhibits the synthesis of
catecholamines by blocking the enzyme tyrosine hydroxylase. The use
of one of these drugs, or a combination, may contribute to symptom
control in patients with functional, unresectable, malignant PCC.289,304,319
Future Drugs
The discovery of molecular pathways and genetic mutations that
characterize malignant PCC has resulted in several phase I and phase
II clinical trials. Multikinase inhibitors, tyrosine kinase receptor
inhibitors, mammalian target of rapamycin (mTOR) inhibitors,
hypoxia-inducible factor (HIF) inhibitors, antiangiogenic agents, and
HER-2/neu inhibitors are among the agents that are currently under
investigation. Treatment of a series of 17 patients with metastatic
PCCs and paraganglioma with sunitinib, a tyrosine kinase inhibitor,
monotherapy resulted in a partial response of 21% and disease stabiliza-
tion of 36%.320 An ongoing open-label trial of sunitinib in patients
with advanced malignant PCC or paraganglioma (SNIPP trial) should
provide further information about the role of sunitinib in the treatment
this aggressive disease. Clearly, novel treatments are needed for the
treatment of patients with malignant PCC and paraganglioma.287
Prognosis
Because metastases or local recurrences after resection of “benign”
disease may occur even 20 years after resection, long-term follow-up
is indicated in all patients with PCC. Plasma metanephrine measure-
ments should be obtained at regular intervals for life. In high-risk
patients, these intervals should initially be shorter.286
It is difficult to predict the prognosis of patients with malignant
PCC. Five-year survival rates are only 20% to 50%. Ten-year survival
rates of 25% have been reported.321 A worse prognosis has been observed
in patients with malignant PCC as compared with malignant para-
ganglioma patients.322 Survival rates decrease with increasing tumor
size; however, there is no difference in overall survival between malignant

PCC and paragangliomas. Prognosis is also affected by tumor size,
metastatic tumor burden, rate of progression, and location of
metastasis.286,288,307,323,324
MULTIPLE ENDOCRINE NEOPLASIA
SYNDROMES
Clinical recognition of MEN syndromes first began in the 1900s. In
the past 10 to 15 years, the molecular underpinnings of each subtype
have been identified, allowing precise genotype-phenotype associations
and genetic testing. Prophylactic surgery plays a key role in the
management of these syndromes, especially for MTC associated with
MEN2A and MEN2B. Therefore, multidisciplinary management,
including genetics professionals, surgeons, and endocrinologists, can
optimize the management of patients with MEN syndromes and their
families. This section summarizes the key clinical features, genetics,
and management issues for the three MEN syndromes: MEN1,
MEN2A, and MEN2B. More detailed discussion of the medical and
surgical management can be found in each of the organ-specific
sections.
Multiple Endocrine Neoplasia Type 1
Wermer first reported a familial aggregation of pituitary tumors,
parathyroid hyperplasia, islet cell adenomas, and peptic ulcer disease
in the 1950s.325 Separately, Zollinger and Ellison reported an association
between unusual small bowel ulcerations and high gastric acid secretion
along with non–insulin-secreting islet cell adenomas.326 Later, this
constellation of tumors became recognized as the MEN1 syndrome.
This syndrome is rare, occurring in 1 in 25,000 individuals.327,328
Clinical Features
MEN1 usually becomes clinically apparent in the 30s and 40s with
hypercalcemia from primary hyperparathyroidism. Because sporadic
primary hyperparathyroidism typically arises in the 50s and 60s, primary
hyperparathyroidism in a younger patient should prompt the clinician
to suspect MEN1. The penetrance of primary hyperparathyroidism
in patients with MEN1 is 80% to 100% by age 40 years. The incidence
rate of MEN1 is 1% to 18% among patients with primary hyper-
parathyroidism.329,330 Tumors of the anterior pituitary occur in 10%
to 60% of patients, with prolactinomas being the most common. The
other common components of the syndrome are pancreatic islet cell
tumors and GI NETs. Often, these are functional islet cell tumors,
such as gastrinomas (50% of individuals) or insulinomas (10% to
13% of MEN1 patients). VIP–secreting tumors (VIPomas), gluca-
gonomas, and somatostatinomas have also been reported.330 Similar
to patients with sporadic gastrinoma, the duodenum is a common
site of gastrinoma in MEN1 patients; however, these tumors tend to
be multifocal.331 Gastric carcinoids affect 10% of patients with MEN1,
and bronchial or thymic carcinoids each occur in 2% of carriers.330,332
Thymic carcinoids are nonfunctional and tend to be aggressive.
Although adrenal hyperplasia and benign adrenal adenomas affect
20% to 40% of carriers, malignant adrenocortical carcinomas are
quite rare. Both benign and malignant adrenal tumors are usually
nonfunctional in MEN1. Finally, nonendocrine tumors, such as
meningioma, ependymoma, leiomyoma, lipoma, and facial angiofi-
bromas or collagenomas, can also be found in patients with MEN1.332
The finding of more than three angiofibromas in combination with
any collagenomas in a single patient is diagnostic of MEN1 with a
sensitivity of 75% and specificity of 95%.333
Genetics and Diagnosis
MEN1 is inherited in an autosomal dominant fashion with equal sex
distribution. Linkage studies map the mutations to the MEN1 tumor
suppressor gene on chromosome 11q13, encoding the MENIN gene.
Several inactivating mutations account for a wide variety of disease
patterns. Disease expression varies even within families. Familial MEN1
Cancer of the Endocrine System  •  CHAPTER 68 1093
is defined as one MEN1 carrier plus at least one first-degree relative
with at least one of the three main endocrine manifestations.
Genetic testing is recommended for individuals who meet clinical
criteria for familial MEN1 or if sporadic MEN1 is suspected because
of early-onset hyperparathyroidism or the constellation of endocrine
tumors. Relatives of known MEN1 carriers should also be tested.
Because the sensitivity of DNA sequencing tests is approximately
70% to 90%, negative genetic testing cannot exclude the syndrome.
Furthermore, at least 10% of MEN1 cases arise de novo.334 In the
absence of positive genetic testing results, MEN1 can be diagnosed in
individuals with two of the three classic endocrine organs (parathyroid,
pancreas-duodenum, or pituitary). Screening consists of biochemical
laboratory tests and imaging directed at the most common tumor sites.
It begins at 5 years of age with serum insulin, glucose, prolactin, and
IGF1. Brain MRI should also be performed at age 5 years and then
every 3 years thereafter. Annual calcium and parathyroid hormone
(PTH) levels are added to the battery of laboratory tests beginning at
age 10 years.335
Treatment
Hyperparathyroidism is often the first and most common endocri-
nopathy detected in MEN1. The disease is aggressive and recurs.
Therefore, treatment consists of subtotal parathyroidectomy, with care
taken to identify each gland and to leave part of the most normal-
looking gland as a remnant. Cervical thymectomy is added to the
procedure to clear parathyroid cell clusters that may grow and cause
recurrence with time.332
Pancreatic and duodenal NETs such as gastrinoma arise as multiple
microadenomas; therefore, historical approaches of distal pancreatec-
tomy or resection of palpable tumors have failed to cure gastrin
secretion.336,337 Patients should be offered surgery when biochemical
markers and/or imaging findings reveal tumors of appreciable size
(≥1 cm), because of the higher metastatic rate in larger tumors. The
operative procedure consists of distal pancreatectomy and enucleation
of tumors in the pancreatic head. For patients with functional tumors
such as gastrinomas, duodenotomy and mucosal resection of duodenal
tumors are added to the pancreatic portion of the procedure. In
addition, some reports have suggested open duodenotomy, often
preceded by endoscopic or intraoperative ultrasound examination,
and subtotal pancreatectomy.338–340 Pancreatic insulinomas can be
managed with enucleation of the pancreatic head tumors plus distal
subtotal pancreatectomy.341
Multiple Endocrine Neoplasia Type 2
The first descriptions of MEN2A appeared in the 1960s and involved
MTC and PCCs.342 At that time, another syndrome that included
mucosal neuromas was also being reported.343 This latter syndrome
later became differentiated from MEN2A and classified as its own
syndrome, MEN2B. Both MEN2 syndromes have a combined
prevalence of 2.5 per 100,000.334
Clinical Features
MEN2A was initially called Sipple syndrome. It is characterized by
MTC, affecting 90% to 100%190 of carriers, PCC in 50%, and
parathyroid hyperplasia in 20% to 30%. Unlike in MEN1, MEN2A
carriers have a milder form of primary hyperparathyroidism. MEN2B
is characterized by early-onset, aggressive MTC, and PCC without
parathyroid hyperplasia. MEN2B patients show mucosal neuromas
of the lips and tongue with a marfanoid body habitus, giving these
patients a very characteristic appearance. These patients also develop
intestinal ganglioneuromas that can cause constipation and GI
dysmotility.332,344
MTC is usually the first manifestation in most patients with MEN2
because of its early age of onset and high penetrance. This cancer
arises from diffuse C-cell hyperplasia concentrated in the upper third
of the thyroid gland, and the tumors are usually multicentric. MEN2B
1094 Part III: Specific Malignancies
carriers have a more aggressive and earlier onset of MTC compared
with MEN2A carriers.335
Approximately 50% of patients with MEN2A and MEN2B develop
PCC, and the frequency depends on the specific underlying RET
mutation.190 Although bilateral disease is common in approximately
30% to 100%, extraadrenal paragangliomas and metastatic disease
are rare.301,345–347 PCCs with MTC occur earlier than sporadic forms,
with a mean age of presentation between 25 and 32 years.346,348
Genetics and Diagnosis
In 1987, genetic linkage studies identified the RET proto-oncogene
on chromosome 10q11.2. The MEN2 syndromes result from missense
germline mutations in this gene.349 Specific codon mutations correlate
with MEN2A and MEN2B (in addition to FMTC). For example,
codon 634 mutations occur in 40% of patients with MEN2A, whereas
codon 918 mutations occur in 95% of patients with MEN2B. MEN2B
mutations correlate with a more aggressive MTC phenotype and MTC
metastases before 12 months of age. An international consensus panel
developed a three-tier risk stratification based on specific codon
mutations. This risk stratification guides the timing of prophylactic
thyroidectomy.334,350,351 It should be noted that somatic RET mutations
are found in approximately 25% of patients with both sporadic MTC
and sporadic PCC.351 RET gene testing should be offered to all members
of MEN2 kindreds. Patients with PCC should also undergo RET
gene testing. However, diagnosis of MTC can be made in the absence
of a RET mutation in patients who have the classic clinical presentation
of MEN2.352 Furthermore, diagnosis should be suspected in patients
with a family history of MTC, younger age at presentation (<35
years), or multicentric tumors.
Ideally, genetic screening and prophylactic thyroidectomy should
preclude the need for diagnosing MTC in MEN2 kindreds. However,
FNA and biochemical testing are sometimes necessary (see section
on MTC). Annual biochemical screening (plasma or 24-hour
urinary metanephrines) and CT scans can exclude PCC in patients
with MEN2.334,335
Management
The timing and extent of prophylactic surgery for MTC among RET
mutation carriers depend on the specific codon mutation. As mentioned,
the MTC associated with MEN2B manifests earlier and behaves more
aggressively. Therefore, patients with MEN2B should undergo pro-
phylactic thyroidectomy before 1 year of age. If thyroidectomy occurs
after 1 year, then prophylactic central neck dissection (level VI) is
added to the procedure. In MEN2A, prophylactic thyroidectomy is
offered before age 5 years (i.e., codon 634 mutations). Surgery can
be offered earlier for higher-risk mutations. When MTC is discovered
clinically, central compartment (level VI) neck dissection is added to
total thyroidectomy. Similarly, compartment-oriented dissection is
indicated when lymph node metastases are discovered clinically. This
may include the lateral neck compartments, if positive nodes are
discovered in these locations.332,352 The mortality from MTC was
reported to be 50% of patients with MEN2B and 9.7% of patients
with MEN2A in one large follow-up study.353 The 10-year survival
rate of MTC has been reported to be 61% to 76%, with old age at
diagnosis, extent of primary tumor, nodal disease, and distant metastasis
as important prognostic factors that predict adverse outcome.352,354–356
PCC most commonly occurs with mutations in codons 634 and
918 but can occur in all MEN2-associated mutations except for codon
768. PCC in patients with MEN2 is treated with adrenalectomy when
the disease becomes clinically evident with elevated catecholamines—
that is, prophylactic adrenalectomy is not indicated. PCCs are rarely
(~15%) the initial manifestation in MEN2 syndromes but do occur
concomitantly with MTC in 25% of patients.357 Consequently,
biochemical testing should be performed before thyroidectomy.
Although PCCs are often bilateral, they develop asynchronously.
A contralateral PCC occurs within 5 years of adrenalectomy in
approximately 30% of patients.358 When bilateral adrenalectomy is
Table 68.8  Multiple Endocrine Neoplasia
Syndromes
Syndrome Gene Inheritance Common Manifestations
MEN1 MENIN Autosomal Parathyroid hyperplasia
dominant Neuroendocrine tumors of
pancreas or foregut
Anterior pituitary tumors
MEN2A RET Autosomal MTC
dominant Parathyroid hyperplasia
Pheochromocytoma
MEN2B RET Autosomal MTC
dominant Pheochromocytoma
Ganglioneuromatosis
Marfanoid body habitus
MTC, Medullary thyroid cancer.
indicated, the patient will require lifelong mineralocorticoid and
glucocorticoid replacement. Because these patients then develop the
complications of long-term steroid medication use and are at risk for
addisonian crisis, some centers prefer to perform cortical-sparing
adrenalectomy. Intraoperative ultrasound guides the extent of resection.
Adrenalectomy can be performed with an open, laparoscopic, or
retroperitoneoscopic approach.358,359
Table 68.8 summarizes the MEN syndromes.
CARCINOID TUMORS
Carcinoid is an English translation of a term first used by German
pathologists in the early 20th century—karzinoide—to describe a
carcinoma-like tumor that appeared to have more indolent behavior
than a carcinoma.360 The term is somewhat of an anachronism now
but remains in common use for describing a well-differentiated NET
that secretes serotonin, which is how the term carcinoid is used in
this section. High-grade or poorly differentiated NETs are now classified
as neuroendocrine carcinomas. Carcinoid tumors are an important
subset of a broader class of neoplasms collectively called neuroendocrine
tumors. Other NETs include medullary carcinoma of the thyroid,
PCC, and pancreatic endocrine tumors. This section approaches the
carcinoid subset of NETs separately from pNETs, which confers
important diagnostic, symptomatic, and therapeutic differences.
Incidence
Data regarding the incidence of carcinoid tumors continue to evolve.
According to data from the SEER database, the incidence of all NETs,
including carcinoid NET, pNET, and poorly differentiated NET has
risen from 1.09 per 100,000 to 5.25 per 100,000 population. This rise
may very well be directly attributable to increased detection because
of modern CT imaging, but the rise in NET diagnosis outstrips the
expectation even when increased detection is taken into account.361
Carcinoid tumors typically have been classified as originating in
the foregut (lung and upper GI tract and, less often, pancreas), the
jejunum and midgut (which includes the ileum and appendix), and
the hindgut (colon and rectum). In a series of more than 13,000
carcinoid tumors reported through End Results Group (ERG), the
Third National Cancer Study (TNCS), and SEER, 66.9% of carcinoids
came from the GI tract, and 25.3% came from the bronchopulmonary
tree. Within the GI tract, 41.8% of tumors came from the small
intestine, 27.4% from the rectum, and 8.7% from the stomach. There
is a slight female predominance (55.1%). White patients tended to
have more bronchial carcinoids than other ethnic groups, and rectal
carcinoids seem to have been overrepresented among patients of African
descent.362
 Cancer of the Endocrine System  •  CHAPTER 68 1095

Table 68.9  Grading Proposal for NET Table 68.11  ENETS Proposal for TNM Staging of
(All Sites)236–238 NET in Small Intestine237
Grade Mitotic Count/10 HPF Ki-67 Index (%) T—PRIMARY TUMOR
G1 <2 ≤2 Tx Primary tumor cannot be assessed
G2 2–20 3–20 T0 No evidence of primary tumor
G3 >20 >20 T1 Tumor invades lamina propria or submucosa and <1 cm
T2 Tumor invades muscularis propria or >1 cm
HPF, High-power field; NET, neuroendocrine tumor.
T3 Tumor invades pancreas or retroperitoneum
T4 Tumor invades peritoneum or other organs
N—REGIONAL LYMPH NODES
Table 68.10  Staging Proposal for NET Nx Regional lymph nodes cannot be assessed
(All Sites)236–238 N0 No lymph node metastasis
Disease Stage T N M N1 Regional lymph node metastasis

I T1 N0 M0 M—DISTANT METASTASES
IIa T2 N0 M0 Mx Distant metastasis cannot be assessed
IIb T3 N0 M0 M0 No distant metastasis
IIIa T4 N0 M0 M1 Distant metastasis
IIIb Any T N1 M0
ENETS, European Neuroendocrine Tumor Society; NET, neuroendocrine tumor.
IV Any T Any N M1

NET, Neuroendocrine tumor.

Table 68.12  ENETS Proposal for TNM Staging of

Pancreatic NET236,237
Clinical Pathology and Staging T—PRIMARY TUMOR
Carcinoid tumors usually are readily identified microscopically. Tx Primary tumor cannot be assessed
Immunohistochemical staining is performed to identify and classify T0 No evidence of primary tumor
these tumors. In addition to immunohistochemical staining to reveal
T1 Tumor limited to the pancreas and <2 cm
specific tumor produced peptides, other semispecific markers, including
neuron-specific enolase (NSE)363 and CgA,364 aid in diagnosis. T2 Tumor limited to the pancreas and 2–4 cm
Appropriate TNM (tumor-nodes-metastases) assessment and discern- T3 Tumor limited to the pancreas and >4 cm or invading
ment of tumor grade are the essential components of a pathologic duodenum, bile duct
diagnosis. As mentioned earlier, nomenclature for NET as a whole T4 Tumor invading adjacent organs
has become challenging. Older nomenclature using “benign” versus
“malignant” or “typical” versus “atypical” carcinoid is thought to be N—REGIONAL LYMPH NODES
inaccurate, because all carcinoids may have some malignant potential. Nx Regional lymph nodes cannot be assessed
The WHO classification divided NET into well-differentiated endocrine N0 No lymph node metastasis
tumors, well-differentiated endocrine carcinomas (WDECs), and poorly N1 Regional lymph node metastasis
differentiated endocrine carcinomas (PDECs). In spite of this improve-
ment over older descriptions, the WHO classification still fell short M—DISTANT METASTASES
in terms of how to predict the malignant behavior of low-grade Mx Distant metastasis cannot be assessed
tumors.365 In an attempt to combine anatomic staging with tumor M0 No distant metastasis
grade, the European Neuroendocrine Tumor Society (ENETS)
M1 Distant metastasis
developed a staging and classification system for NETs that has proven
useful for prognostication at each anatomic site366,367 (Tables 68.9 ENETS, European Neuroendocrine Tumor Society; NET, neuroendocrine tumor.
through 68.12). SEER data suggest that across all stages and sites,
the 5-year survival in patients with carcinoid tumors is 67.2%. Carcinoid
tumors of the rectum typically have lower risk of recurrence and better
5-year survival (88.3%) than other GI tract carcinoids (67.5%) and the GI tract accounting for more than two-thirds of primary tumors.
bronchopulmonary carcinoids (73.5%).362 There are reports of carcinoid tumors of the bladder, breast, ovary,
Tumors of mixed histology, such as goblet cell or adenocarcinoid testis, and thymus.362 As noted earlier, biopsy confirmation, with
tumors of the GI tract, have both mucinous and neuroendocrine appropriate staging and grading, is critical because the biologic behavior
differentiation. These tumors are often more aggressive than typical of low-grade NETs is typically more indolent than that of adenocar-
GI carcinoids and require staging and management similar to those cinoma of any of the aforementioned sites.
of adenocarcinoma.368
Diagnosis
Anatomy
The diagnosis of carcinoid tumor is made by finding tumor or symptoms
Carcinoids are thought to arise from the Kulchitsky cells in the crypts related to mass effect, biologically active peptides, or urinary tumor
of Lieberkühn of the gut, and are disseminated in the endobronchial markers (Fig. 68.7). Although measurement of 5-hydroxyindoleacetic
mucosa.369 These tumors can arise from nearly any anatomic site, with acid (5-HIAA) is the most common and reproducible test for the
1096 Part III: Specific Malignancies

Symptom/finding

Diarrhea Tumor with no syndrome

Flushing
Hypotension
Rarely
Tumor location unclear Tumor location apparent
Heart disease
Pellagra
Asthma Staging
Osteoarthropathy
Contrast radiography or CT
scan of abdomen and chest
Consider: carcinoid

No elevation of urinary Urinary 24-hour Metastatic tumor Localized tumor

24-hour 5-HIAA 5-HIAA > 6 mg/24 hr
(> 30 mg/24 hr in
patients with diarrhea Tissue diagnosis Tissue diagnosis
Consider or malabsorption)
Islet tumor or carcinoid
with no serotonin Surgical resection
production (rare) Carcinoid tumor
Cure

No carcinoid syndrome Carcinoid syndrome present

Pharmacologic therapy
Tumor bulk Symptomatic liver to decrease symptoms
Observation Somatostatin analogue
symptoms metastases
?Alpha-interferon

Cytoreductive Cytoreductive surgery or Progression

surgery hepatic artery ligation or
hepatic arterial embolization
± chemotherapy
Progression Surgical therapy Nonsurgical
therapy

Metastases any site Liver mets

Cytoreductive Cytoreductive surgery or

surgery hepatic artery ligation or
hepatic arterial embolization
± chemotherapy

Progression Progression Progression

Systemic therapy, chemotherapy or biologic response

modifiers

Figure 68.7  •  Algorithm of diagnosis and treatment of carcinoid tumors. CT, Computed tomography.
 Cancer of the Endocrine System  •  CHAPTER 68 1097

presence of carcinoid syndrome; significantly elevated levels of 5-HIAA Anterior Posterior

usually occur only after there is a 20% to 25% liver tumor burden.
In most laboratories, the upper limit of normal for 24-hour urinary
5-HIAA excretion is 6 to 10 mg. In one study, 5-HIAA measurements
were 100% specific and 73% sensitive for the presence of carcinoid
syndrome.370 Not all patients with carcinoid tumor have the associated
syndrome, and the sensitivity of assays for detecting the presence of
tumor alone is inadequate. Although markedly elevated 5-HIAA in
the urine is specific for carcinoid tumor, a low-level false-positive
increase of 5-HIAA may be seen in patients with noncarcinoid tumor
and after intake of certain foods (e.g., bananas, walnuts, and pecans)
and serotonin reuptake inhibitors (e.g., sertraline [Zoloft], fluoxetine
[Prozac]) and other medications (e.g., acetaminophen, salicylate,
guaifenesin).371–373 5-HIAA also may be elevated to low abnormal
levels (<30 mg) in patients with diarrhea or malabsorption from any
cause. In addition to excellent specificity and high sensitivity, 5-HIAA
measurement has a high level of consistency, both in individual patients
and among groups. In the Mayo Clinic series, the level of 5-HIAA
excretion remained constant in a group of 85 patients in whom paired
determinations were performed during a 10-day period.374 Moreover,
in any given patient, the level of 5-HIAA secretion is a relatively
accurate indicator of tumor bulk. A novel test of plasma 5-HIAA has
been developed in which results were significantly correlated with the
urine 5-HIAA.375 In a study that included 500 specimens of consecutive Figure 68.8  •  Indium-111 (111In) octreotide scan. Patient with metastatic
raised plasma CgA, urine 5-HIAA, and plasma neurokinin A (NKA), carcinoid with octreotide scan showing bony and visceral metastases with
CgA remained the best general circulating marker for NETs.376 Serum anterior and posterior views.
NSE and CgA levels have been shown to correlate with the presence
and natural history of GI NETs.363,364 For midgut carcinoids, which
produce high levels of serotonin, the sensitivity of CgA levels is only
slightly better than that of urinary 5-HIAA levels. However, for flushing.387,388 Serotonin may be responsible for intestinal hypermotility
foregut- and hindgut-derived tumors, CgA levels are highly sensitive and hypersecretion, but it probably does not cause the characteristic
compared with urinary 5-HIAA levels.377 However, sensitivity and flushing that occurs with the carcinoid syndrome.389 Vasodilation,
specificity of CgA depends on the cutoff value.378,379 Like 5-HIAA, which causes flushing, can be caused by one or more substances released
CgA may be elevated in nontumoral conditions such as atrophic by the tumor cells, including bradykinin, substance P (midgut carci-
gastritis, proton pump inhibitor (PPI) use, liver or kidney dysfunction, noids), tachykinins, and prostaglandins. The symptoms of the carcinoid
and inflammatory bowel disease.377 CgA may be an important early syndrome vary in frequency. Flushing is most frequent, followed by
biomarker of response to some types of therapy. diarrhea, heart disease, and bronchoconstriction. Presence of carcinoid
As CT and MRI scanning technologies improve, the ability to syndrome and heart disease are adverse prognostic indicators for
localize even small tumors has improved considerably and may allow survival.390
for more precise imaging of primary and metastatic lesions.380 Most
carcinoid tumors are highly vascularized and enhance with iodinated Flushing
contrast agent during the early arterial phase.381 However, for metastatic Two types of flushing are accepted as accompanying the usual metastatic
liver disease, MRI is probably the most sensitive method.382 Localization ileal carcinoid. It is thought that any of the activities that drive plasma
of carcinoid and islet cell tumors has been investigated by nuclear catecholamines, which instigate the flushing, may be mediated, in
medicine techniques (Fig. 68.8).383,384 The sensitivity of somatostatin part, by peptides such as the tachykinin substance P or the amine
receptor or octreotide scanning (OctreoScan) is reported to be up to serotonin. Stressors associated with hypercatecholemia include exercise,
87%, with a positive predictive value of 100%, making it a useful excitement, emotion, ethanol, and decongestants such as ephedrine. One
imaging study for carcinoid tumors.383 Early indication of a possible type of flushing is red and diffuse, involving the face and upper body;
response to octreotide-based therapy (see later) may also increase the it is of short duration and can be provoked by alcohol, excitement,
usefulness of octreotide scanning. Recently developed and approved emotional stress, and catecholamine release.391,392 The other is more
by the FDA, gallium-68 (68Ga)–DOTATATE PET-CT imaging has prolonged, produces venous dilation and a purplish hue about the
a higher spatial resolution than conventional OctreoScan and better face, and can give rise to permanent dilation of facial veins and even
sensitivity in detection of small tumors.385 telangiectasia. This flush is more commonly precipitated by alcohol
ingestion. Because infusion of serotonin does not cause either type of
Symptoms flush, it has been suggested that the kinins cause this symptom.393 Brief
flushes may be caused by catecholamine-induced release of vasoactive
Carcinoid Syndrome substances such as kallikreins; these flushes can be blocked effectively
Many patients with metastatic carcinoid tumor manifest the signs by α-adrenergic blocking agents.394 Carcinoid of the foregut produces
and symptoms of abnormal hormone production—the malignant a more intense and erythematous flush (as seen in a serotonin burst),
carcinoid syndrome.386 Serotonin (5-hydroxytryptamine [5-HT]), sometimes associated with itching, conjunctival suffusion, and facial
synthesized by the tumor from tryptophan and metabolized to 5-HIAA, edema suggestive of histamine release. Occasionally, gastric carcinoids
which appears in the urine, is particularly important because urinary cause an urticarial reaction, which may be inhibited by the histamine
5-HIAA levels are used to monitor the course of carcinoid syndrome. H1- and H2-receptor antagonists diphenhydramine and ranitidine.395
However, the relation of serotonin levels to symptoms of the clinical
carcinoid syndrome is uncertain. Carcinoid tumors also release the Diarrhea
enzyme kallikrein, which acts on α2-globulin to produce bradykinin The diarrhea of carcinoid syndrome does not necessarily correlate
and its precursor, lysyl-bradykinin, both of which can induce with flushing. Diarrhea appears to be related to increased gut motility
1098 Part III: Specific Malignancies
rather than to secretion of fluids. Diarrhea of the carcinoid syndrome
rarely is of high volume and therefore typically requires only mild
palliative antidiarrheal therapy. Although abdominal cramping can
be associated with this form of diarrhea, other possibilities for abdominal
pain must be considered, including intermittent partial small bowel
obstruction secondary to mesenteric fibrosis or bowel obstruction
secondary to tumor bulk.
Heart Disease
The cardiac disease associated with the carcinoid syndrome is an
endomyocardial fibrosis typically involving the right side of the heart,
although left-sided lesions have been described in the setting of patent
foramen ovale.396 Fibrotic deformation of the tricuspid and pulmonary
valves usually leads to pulmonary stenosis and tricuspid insuffi-
ciency.397,398 Carcinoid heart disease is a late complication of carcinoid
tumors, with the disease developing after an average of 5 years from
diagnosis of carcinoid tumor. The prevalence of carcinoid heart disease
has fallen from 50% to 70% of patients with carcinoid syndrome to
20%, likely as a consequence of the use of octreotide and other agents.398
Screening patients with carcinoid tumors with brain natriuretic peptide
or echocardiogram can be considered if symptoms of heart disease
are present.399–401
Other, relatively rare signs and symptoms may be associated with
carcinoid syndrome. Bronchoconstriction may occur in both pulmonary
and extrapulmonary carcinoid, and usually is associated with flushing.
The classic triad of dermatitis, dementia, and diarrhea seen with pellagra
occasionally has been identified. This syndrome is secondary to niacin
deficiency as a result of shunting of dietary tryptophan from niacin
synthesis to indole synthesis. It is very rare in the United States and
other developed countries because of better overall nutrition compared
with developing and underdeveloped countries. It is treated simply
with nicotinamide from nonprescription vitamin supplements.
Therapy
Management of carcinoid tumors depends not only on traditional
methods of dealing with the tumor itself, but also on management
of associated medical problems typically caused by overproduction of
hormonally active peptides. When curative surgery is not possible,
surgical debulking may result in symptomatic improvement.
Surgery
Surgery has an important role throughout the course of carcinoid tumor
management. Resection of the primary tumor and of associated resect-
able nodal metastases is primary therapy.402 Surgical approaches clearly
differ by site. Carcinoids of the appendix commonly are discovered
incidentally. Most are smaller than 1.0 cm and are cured by surgical
resection. In the Mayo Clinic series, no tumor of 1 cm or less recurred
after resection. Therefore, appendectomy alone is adequate treatment.
With the uncommon large appendiceal carcinoid (i.e., >2 cm) or
those with mesoappendiceal invasion, a true cancer operation (e.g.,
right hemicolectomy) is required.403,404 Small rectal lesions may be
resected endoscopically. However, tumors larger than 2 cm in diameter
require standard cancer operations, such as a low anterior resection or
abdominoperineal resection. However, controversy still exists regarding
intermediate-sized tumors (1–2 cm confined to mucosa and submucosa).
Endoscopic submucosal dissection (ESD) has been found effective
in 239 patients with rectal carcinoid smaller than 2 cm.405 In small
bowel tumors, small bowel resection with removal of mesenteric nodes
is recommended. It follows that the surgical approach to bronchial,
gastric, or gonadal carcinoid will depend on the location and stage at
presentation. These tumors often elicit a mesenteric fibrosing reaction,
in which the mesentery becomes shortened and the bowel kinked,
frequently causing partial small bowel obstruction.406 Pain or physiologic
abnormalities secondary to partial bowel obstruction may be greatly
relieved by palliative surgical resection, bypass, or both. The indolent
course of carcinoid tumors mandates a high index of suspicion for
such complications and an aggressive approach in considering surgical
palliation. Disease-specific 10-year survival rates of small intestine
NETs were reported in a SEER cancer registry study, ranging from
95% for stage I to 42% for stage IV.407 However, even with metastatic
disease, 5-year and 10-year survival rates of 40% to 85% and 40%
to 60%, respectively, have been reported.407–411
Management of hepatic metastases is critical. The goal of therapy
is to control symptoms and improve quality of life. In many patients,
bulky hepatic metastases constitute most of the tumor burden, so
tumor reduction may, at the least, diminish production of peptides
that promote the carcinoid syndrome, in addition to extending sur-
vival.412 Historically, resection is recommended if at least 90% of the
tumor can be feasibly removed. The indications to proceed with hepatic
metastasectomy are more liberal in carcinoid tumors than in metastases
from other solid tumors. In a very large multiinstitutional series of
339 patients who underwent hepatic resection for NET liver metastasis,
5-year and 10-year survival rates were 74% and 51% respectively.413
This is consistent with the findings of a meta-analysis of cytoreductive
partial hepatectomy for carcinoid metastases, in which surgical debulk-
ing yielded a 5-year survival rate greater than 70% and resolution of
carcinoid symptoms in 86% of patients.414 In patients whose extrahepatic
disease has been eliminated, liver transplantation may be an option
as well.414a,414b
Radiation Therapy
Radiation therapy seldom is used to treat carcinoid tumor or carcinoid
syndrome. Patients with carcinoid syndrome often have extensive
hepatic metastases, and the dose-limiting toxicity of hepatic radiation
limits its usefulness. Trials of stereotactic body radiotherapy (SBRT)
have shown that doses up to 60 Gy can be given in a focused way to
oligometastatic disease.415 Trials looking at disease-specific survival
after SBRT are ongoing.
Palliative treatment of bone metastases is an indication for radiation
therapy.
Antihormonal Therapy
When the symptoms attributed to serotonin are mild, they can be
managed successfully over lengthy periods with simple measures, such
as administration of opiates and diphenoxylate hydrochloride with
atropine.
About 80% of carcinoid tumors express somatostatin receptors,
which can be determined with OctreoScan or 68Ga-DOTATATE
PET-CT. Intravenous or subcutaneous somatostatin inhibits carcinoid
flush and significantly improves diarrhea in over 80% of patients416
but is not practical for therapy because it has a half-life of less than
2 minutes.417 Synthetic octapeptide analogues of somatostatin, octreotide
acetate, lanreotide, and vapreotide have longer half-lives and can be
given subcutaneously every 4 to 8 hours to maintain the action of
somatostatin. In addition, the long-acting repeatable agent Sandostatin
LAR (octreotide acetate for injectable suspension) has been shown to
be highly effective in control of both carcinoid flushing and diarrhea.418
Somatostatin influences the inhibition of numerous GI hormones,
gastric secretion, gastric and small intestinal motility, splanchnic blood
flow, pancreatic enzyme secretion, intestinal nutrient absorption, and
gallbladder contractility.419 Kvols and colleagues first described the
use of the somatostatin analogue octreotide in therapy for carcinoid
syndrome.420 Fifty-seven patients with carcinoid tumor and carcinoid
syndrome were treated with daily doses of octreotide acetate, ranging
from 100 to 1127 mg (mean, 414 mg). Flushing was abolished in
most patients, and diarrhea was controlled adequately in approximately
75%. Control of symptoms usually was associated with a decrease in
the urinary 5-HIAA levels, but reduction in tumor bulk was not seen
consistently. Increased doses of somatostatin may partially overcome
resistance.421
A randomized, double-blind, placebo-controlled trial of octreotide
LAR in midgut NETs showed a significant prolongation in PFS from
6 months in the placebo arm to 14.3 months in the Sandostatin LAR

arm.422 The improvement in PFS was most pronounced in patients
with resected primary tumors and relatively low (<10% liver involve-
ment) tumor burden. An effect on overall survival could not be reliably
determined in this population. Furthermore, in randomized phase III
trials, octreotide and lanreotide have been proven to inhibit tumor
growth.422,423 Data from a randomized controlled study of the effect
of octreotide on long-term survival among patients with metastatic
NETs showed no difference between the octreotide and placebo
groups.424 There remains some question as to how long therapy with
octreotide should continue after disease progression, or if it should
continue indefinitely for symptomatic relief.
Somatostatin analogues are usually well tolerated.419,420,425 Long-term
therapy may predispose to the formation of gallstones; the drug
promotes cholelithiasis by inhibition of cholecystokinin release and
a resultant inhibition of gallbladder emptying. Early reports suggested
a high rate of cholelithiasis for patients on somatostatin and recom-
mended elective cholecystectomy, when feasible.425 However, other
reports have indicated that cholelithiasis is rarely symptomatic and
that cholecystectomy can be performed selectively.426,427
Chemotherapy
Because the disease is indolent, the role of cytotoxic chemotherapy
has been somewhat limited. Antineoplastic therapy may be called for
in patients with tumors that have a high Ki-67 level or with severe
symptoms of carcinoid syndrome uncontrollable by other methods.
High-grade NETs should be treated with a platinum doublet akin to
treatment in small cell lung cancer.428,429
For lower-grade tumors, cytotoxic chemotherapy is much less
effective. With single agents, the response rates of greater than 10%
were seen with only three adequately tested drugs: doxorubicin, 7 of
33 (21%); 5-FU, 5 of 19 (26%); and dacarbazine (DTIC), 2 of 15
(13%).394 A larger series of patients was involved in a phase III study
by the Eastern Cooperative Oncology Group (ECOG)430 comparing
5-FU plus doxorubicin (FA) to 5-FU plus streptozocin (FS). Response
rates (33% versus 26%, respectively) and survival for the two treatment
arms were not significantly different. A subsequent ECOG trial
comparing dose-modified FS and doxorubicin alone also demonstrated
equivalent response rates. In the largest randomized ECOG trial of
208 patients, FA and FS therapies were associated with response rates
of 13% and 16%, respectively; there was a trend toward improved
survival in the FS group (24 months versus 16 months for FA;
P = .11).431
Interferon
Interferon has historical significance as a possible treatment for carcinoid
tumors, but its toxicity and relative lack of efficacy limit its use. In
early trials, response rates ranged from 20% to 55%, with response
gauged by decrease in symptom burden rather than radiographic
response.432,433 Little radiographic response has been shown with
interferon. Patients with carcinoid tumors treated with interferon may
develop a wide variety of autoimmune diseases, such as thyroid disease
(thyrotoxicosis, hypothyroidism), pernicious anemia, and vasculitis.
Accounting for these toxicities, the lack of significant benefit, and the
presence of more effective therapies, the use of interferon for carcinoid
tumors is not common. Biochemical response was reported to be
around 75% in patients treated with a combination of interferon and
octreotide after failure of octreotide alone.434,435 As a result, both ENETS
and the North American Neuroendocrine Tumor Society (NANETS)
guidelines include interferon-α as a second-line therapy for functioning
GI NETs after failure of a somatostatin analogue.436,437
Hepatic-Directed Therapy
Surgical metastasectomy for liver tumors is ideal, but possible in
only 10% to 20% of patients with metastatic disease.438 Carcinoid
tumors have a propensity to metastasize to the liver, and derive a
significant component of their blood supply preferentially from
hepatic arterial vasculature. Targeting the hepatic arterial supply with
Cancer of the Endocrine System  •  CHAPTER 68 1099
embolization, chemoembolization, or radioembolization capitalizes on
this anatomic principle. Although the data are not as robust as they
are for colorectal cancer metastases or hepatocellular carcinoma, a
number of case series have shown symptomatic benefit, improvement
in circulating biomarkers, and radiographic responses in NET. The
largest series to date is from the MD Anderson Cancer Center, where
69 patients with carcinoid tumors were treated with either bland
embolization or chemoembolization. A radiographic response was
seen in 46 patients (66.7%), with a median PFS of 22.7 months.439
Other series have reported symptomatic improvement in more than
90% of patients receiving intraarterial therapy.440 Emerging treatments
with radioactive microspheres (yttrium-90 [90Y]) have shown some
efficacy as well.441 Radiofrequency ablation also has been used, with
documented improvement in symptoms, although the case series are not
as large.442,443
Targeted Agents
Inhibition of mTOR demonstrated preclinical efficacy in carcinoid
tumors,444 and everolimus, an mTOR inhibitor, recently demonstrated
a survival benefit in pNET (see later).445 The multinational RADIANT-2
(RAD001 in Advanced Neuroendocrine Tumors, Second Trial) study
randomized patients to octreotide plus everolimus versus placebo. In
429 enrolled patients, an improvement in PFS was noted (16.4 months
versus 11.3 months; P = .026). More biochemical improvements in
5-HIAA and CgA levels were seen in the everolimus arm, but there
was no difference in radiographic response rate. Median overall survival
had not been reached in this trial by the time of the publication of
its findings, and the results may be confounded because patients on
placebo were allowed to cross over to everolimus. The subsequent
RADIANT-4 trial compared everolimus alone versus placebo for
patients with advanced, progressive, nonfunctional NETs of the lung
and GI tract. Everolimus was associated with improved PFS (11.0
versus 3.9 months; P < .0001) and overall survival (hazard ratio [HR]
= 0.64; P = .04). These findings held in subgroup analyses of both
lung and GI tumors.446 In February 2016, the FDA approved everolimus
for the treatment of adults with progressive, locally advanced, well-
differentiated, nonfunctional NETs of GI tract origin. Stomatitis,
rash, and fatigue were the most common adverse events associated
with everolimus.447
The addition of bevacizumab to octreotide showed a response rate
of 18% in a phase II study, with improvement in PFS when compared
with interferon.448 Larger-scale studies have not yet been performed.
Sunitinib has shown efficacy in phase III studies of pNET,449 but
limited response rates were seen in a carcinoid subset when examined
in a phase II setting.450 More studies exploring potential targets for
carcinoid tumors are urgently sought.
Radionuclide Therapy
Research in radiopharmaceuticals has yielded an emerging treatment
option for tumors that overexpress somatostatin receptors. Coupling
receptor-binding somatostatin analogues (DOTATOC for octreotide,
DOTATATE for octreotate) with 90Y or lutetium-177 (177Lu) has
been explored in clinical trials. 90Y appears to have greater efficacy
in larger tumors, and 177Lu in smaller tumors. Phase II data suggest
a partial response rate of 23% by RECIST (Response Evaluation
Criteria in Solid Tumors) for 90Y DOTATATE,451 and 30% for
177
Lu DOTATATE.452 More than 50% of patients in these studies
experienced a clinical response in terms of symptom improve-
ment.451,452 Combining 90Y and 177Lu, a cohort study was performed
in Switzerland that demonstrated an overall survival of 5.51 years.
Preliminary results of the NETTER-1 trial, in which 230 patients with
inoperable somatostatin receptor–positive midgut NET progressive
disease in whom standard octreotide therapy had failed, showed that
177
Lu DOTATATE was associated with improved PFS compared with
octreotide alone.453 Toxicities of these agents include myelosuppression,
and a 10% rate of severe, potentially life-threatening renal toxic-
ity.454 These agents are not available in the United States outside of a
1100 Part III: Specific Malignancies

clinical trial at this time but are growing in popularity where offered
in Europe.
PANCREATIC NEUROENDOCRINE TUMORS
The advent of radioimmunoassay (RIA), immunofluorescence, and
other techniques for identifying peptide hormones has expanded our
knowledge of the prevalence and endocrine effects of pNETs. A
population-based study has shown an increased incidence of NETs
from 2.4% to 5.8% per 100,000 per year.455
The pancreatic islet contains α-cells (glucagon), β-cells (insulin),
δ-cells (somatostatin), and enterochromaffin cells (serotonin). These
cells are all part of the neuroendocrine system, and tumors so derived
secrete a wide variety of polypeptides. Some of these peptides share
the characteristics and functions of classic hormones: (1) their release
follows a physiologic stimulus; (2) they have the ability to affect
response in a distant organ; and (3) these effects are mimicked by
exogenous infusion of the hormone. By contrast, some abnormal
peptides produced by islet cell tumors have no known clinical
hormonal effects. These peptide-secreting tumors are, for the most
part, nonautonomous. This is thought to be a result of tumor cell
regulation by somatostatin and its predominant tumor cell recep-
tor somatostatin receptor subtype 2.456 In evaluating patients with
pNET, it is important to understand that there appear to be two
different etiologies. The first group consists of those patients who
experienced their tumors stochastically, in the absence of significant
personal or family history of endocrine disorders. The second group
includes those with clear evidence of an inherited predisposition
to multiple neoplasias of the endocrine system in an autosomal
dominant pattern. The latter patients tend to have a more indolent
course than those with sporadic tumors. These MEN syndromes were
described earlier. Body mass index, diabetes, smoking, and alcohol
consumption have been described as risk factors for pNET in two
meta-analyses.457,458 As with carcinoid tumors, the approach to the
patient with a pNET must be individualized, balancing management
of the effects of hormone production with symptoms of tumor bulk.
In any individual patient, either management issue may predominate.
Treatment should be directed not only by the presence of symptoms,
but also by a consideration of the relatively lengthy natural history of
pNET (Fig. 68.9).

Symptom/finding

Pancreatic mass Hypoglycemia Gastric ulceration Glucose intolerance Severe watery

No systemic syndrome (diaphoresis, ± diarrhea diarrhea
seizure, coma) Hypokalemia
achlorhydria
Basal acid output With dermatitis Cholelithiasis (WDHA)
Carcinoid >15 mEq/h (migratory ± steatorrhea
Measure Nonfunctioning Fasting plasma necrolytic
pancreatic islet cell (>60% gastriN >1,000 erythema)
polypeptide malignant) pg/mL
or
+ secretin test Glucagon Elevated Pancreatic tumor
+ calcium infusion levels usually somatostatin ↑ VIP
test high
Ppoma Provocative
(>60% test rarely
Gastrinoma necessary Somatostatinoma VIPoma
malignant) (60%–90% malignant) (80% malignant (80% malignant
60% pancreatic) 90% pancreatic)

Duodenum Pancreatic
Suspect insulinoma (20%) (40%–50%)

Glucagonoma
(60% malignant
Glucose < 50 mg/dl Hypoglycemia + Serum >99% pancreatic)
Elevated plasma ↑ insulin sulfonylurea
insulin levels
↓ proinsulin
Elevated proinsulin ↓ c-peptide
Elevated or normal + insulin
c-peptide antibodies

Insulinoma Surreptitious Surreptitious oral

(10%–15% insulin use hypoglycemia use
malignant >99%
pancreatic)

Figure 68.9  •  Diagnosis of pancreatic islet cell tumors. Ppoma, Pancreatic polypeptide-secreting tumor; VIP, vasoactive intestinal peptide; VIPoma, vasoactive
intestinal peptide secreted by a pancreatic islet tumor.

Diagnosis and Imaging
Specific syndromes and diagnostic tests for each of the more common
pNETs are discussed separately later. However, a few generally applicable
principles should be understood. Where possible, tissue confirmation
with biopsy demonstrating characteristic neuroendocrine staining
(discussed earlier) is critical. RIA of peptides obtained by selective
venous catheterization may be helpful in localizing tumors and may
demonstrate the presence of metastatic spread, particularly in patients
with gastrinomas that are occult on imaging (Zollinger-Ellison syn-
drome). NSE or CgA is useful in detecting and following therapeutic
response in pNET, but there are limitations in diagnostic specificity,
mentioned earlier, with regard to carcinoid tumors.363,364
For larger tumors, CT scans are particularly helpful in tumor
localization and assessment of metastatic burden. CT scan can reveal
lesions as small as 4 mm with sensitivity greater than 80%; however,
sensitivity decreases with tumor less than 2 mm.459,460 Because many
pNETs and their metastases may be small, the procedure may not be
adequately sensitive, and multimodality imaging may be required.461
As with most endocrine neoplasms, pNETs have a rich vascularity,
so characteristic enhancement patterns on multiphase CT and MRI
may helpful in differentiating these tumors from adenocarcinoma.
Improvements in technology and technique have improved the
diagnostic usefulness of MRI. pNETs typically have high signal intensity
on T2-weighted and fat-saturated images, coupled with low intensity
on T1-weighted and fat-saturated images, and arterial enhancement
with gadolinium contrast. This constellation of imaging findings has
a sensitivity of 94% for intrapancreatic lesions.462–465
Ultrasonography is of some use in imaging both pancreatic primary
tumors and hepatic metastases and may be used to guide percutane-
ous biopsy of suspicious liver lesions. Endoscopic ultrasonography is
somewhat operator dependent but may allow for image-guided FNA
for tissue confirmation of tumors.466 In a prospective series of 37
patients, endoscopic ultrasonography was highly sensitive and specific
for pancreatic endocrine tumors, as ultimately confirmed with surgical
excision.467 68Ga-DOTATATE PET-CT has been shown to be effective
in identifying the primary lesion in patients with metastatic disease.385
Staging
Like the carcinoid subset of NET, staging guidelines for pNET have
been suggested that offer greater prognostic potential than the staging
for pancreatic adenocarcinoma (see Table 68.12).
Specific Pancreatic Neuroendocrine
Tumor Subtypes
Insulinoma
Insulinomas are the most common functional pNET.468 The average
age of presentation of insulinoma is in the fifth decade, with a 57%
female preponderance.469 An incidence of 4 cases per million per year
has been reported.470 The sine qua non in diagnosing this syndrome
is fasting or inappropriate hypoglycemia accompanied by a relatively
high plasma insulin level.471,472 Other tests have been proposed,
including a hypernormal response to tolbutamide, the response of
plasma insulin to an infusion of calcium gluconate, and the ratio of
proinsulin471,473 to insulin in the plasma, which occasionally is not
useful because the absolute insulin level is not elevated in all insulino-
mas. In addition, measurement of β-hydroxybutyrate is helpful in
diagnosing insulinomas owing to the antiketogenic effect of insulin.
The key to the diagnosis is a high index of suspicion.
Sporadic insulinomas usually are single, smaller than 2 cm, and
benign; approximately 10% are malignant with metastatic distribution
into lymph node, liver, and bone.474,475 Differentiation of benign from
malignant tumors is difficult based on the pathologic features alone,
but the presence of metastases defines malignancy. In patients with
malignant disease, proinsulin may be increased in plasma or circulating
Cancer of the Endocrine System  •  CHAPTER 68 1101
human chorionic gonadotropin.476,477 The typical patient with symptoms
of insulinoma has a single small, pancreatic nodule. In atypical cases,
with multiple primary endocrine tumors, including an insulinoma,
MEN1 syndrome should be suspected.478 Insulinomas are found with
equal proclivity throughout the pancreas.479
These tumors usually are imaged with high-resolution multiphasic
CT, MRI, or abdominal ultrasonography as the initial study. Occult
lesions can be identified with techniques such as endoscopic ultrasound
and selective arteriography and portal venous sampling.469 If these
studies are negative, some authors recommend proceeding with
exploration with manual palpation of the pancreas and intraoperative
ultrasound examination, citing success rates greater than 90% at initial
exploration.
Surgical resection usually is curative because of the small size and
low metastatic potential of insulinomas. The type of resection indicated
depends on the size and anatomic relationship of the tumor to the
surrounding vasculature. Laparoscopic surgery can be done for small,
solitary tumors that have been localized preoperatively.480 Enucleation
is possible, but for larger tumors, a formal pancreatectomy is necessary.
As in other NETs, partial resection may afford palliation in patients
whose symptoms are disabling or cannot be controlled with nonsurgical
modalities, with long-term remission rates of 77% to 100%.481
A patient with unresectable insulinoma and recurrent episodes of
hypoglycemia often benefits from appropriate diet and administration
of an insulin antagonist. Frequent feedings between meals and at
bedtime are administered with sufficient glucose to control symptoms.
Adjustments in the carbohydrate content of the diet may be required,
depending on the reactivity of the individual tumor, because the
stimulus of a large glucose load may lead to an exaggerated release of
insulin.482 Parenteral glucose supplementation becomes an important
adjunct in frequent or sustained hypoglycemic attacks; in emergencies,
rapid injection of 50% glucose can be required.
Octreotide is valuable in the general management of all hormone-
producing NETs and has been found to reduce plasma insulin levels
in at least 65% of patients with insulinoma.483 Octreotide is especially
useful when there are insulinoma metastases, because there appears
to be upregulation of somatostatin receptor subtype 2 of the metastatic
lesions (whereas as few as 17% of the primary lesions express this
receptor).479 Initiation of octreotide acetate requires close monitoring
when used in insulinoma therapy, because up to 60% of primary
tumors may not have SST2 receptors, and hypoglycemia may worsen.484
Corticosteroids, human growth hormone, and glucagon have been
useful palliative agents in individual patients.485,486 However, because
of their limited effectiveness, they are best used in combination with
other antihormonal measures. Furthermore, glucagon stimulates
pancreatic insulin secretion and may cause paradoxical exacerbation
of a hypoglycemic episode.
Diazoxide’s potent hyperglycemic properties, originally recognized
during its use as an antihypertensive agent, have now been extended
to the palliation of insulinoma and leucine-sensitive hypoglycemia of
infancy.487 Its principal action is to inhibit insulin release directly from
the β-cell. It also may have an extrapancreatic hyperglycemic effect
and cause marked edema and hirsutism. Diazoxide is administered
orally in divided doses, ranging from 100 to 1000 mg/day. Although
the plasma insulin level often can be reduced to a level that causes
no symptoms, the tumor will continue to grow and metastasize if
malignant, because diazoxide lacks anticancer activity. Insulinomas
have excellent long-term outcomes; 20-year survival has been reported
in 90% of patients with metastatic insulinomas.488
Glucagonoma
Glucagon from pancreatic α-cells plays an important role in modulating
serum glucose concentrations. Unregulated secretion of glucagon by
α-cell tumors produces a distinctive clinical syndrome. An annual
incidence rate of 0.01 to 0.1 new cases per 100,000 population per
year has been reported.489 A cutaneous rash, described as a necrotizing
migratory erythema, is the most characteristic feature and is present
1102 Part III: Specific Malignancies
in approximately 70% of patients.490,491 Mild insulin-resistant diabetes
and weight loss attributable to the catabolic effects of glucagon also
are seen. Glossitis, cheilosis, and venous thromboses can develop.
Glucagon inhibits intestinal motility, and the glucagonoma syndrome
often includes ileus and constipation. Because symptoms commonly
are mild and nonspecific, the tumor often is recognized late, when
metastases are present.491 Most tumors have grown to larger than 4 cm
at diagnosis, and 50% to 80% are metastatic.492 Most glucagonomas
are sporadic; only 3% are associated with MEN1, and fewer are linked
with von Hippel-Lindau syndrome.493,494
The diagnostic test for glucagonoma is the finding of a high plasma
glucagon concentration (normal, <60 pg/mL). In patients with glu-
cagonoma, the plasma hormone level typically is markedly elevated
and often is greater than 1000 pg/mL. The diagnosis is further suggested
by failure of glucose to suppress glucagon, by an abnormal rise in
plasma glucagon following infusion of arginine, by the presence of
hypoaminoacidemia, and, if tumor is available, immunoperoxidase
staining for glucagon. Reviews have suggested that the tumor is more
common in women and typically manifests in the fifth and sixth
decades.492,495 Symptoms persist for many years before the diagnosis
is made; survival, even with metastatic disease, may be lengthy. The
primary tumor is in the tail or body of the pancreas in 50% of patients
and in the head of the pancreas in 8% of patients; the remaining 42%
of patients have diffuse involvement. CT scans and MRI are useful
in identification of the primary tumor, as is somatostatin receptor
scintigraphy (SSRS) because most are larger than 3 cm at presenta-
tion.496,497 Presence of calcification in CT indicates lymph node
metastasis.498 The tumor is resectable for cure in less than one-third
of cases, and recurrence after resection, mainly in the liver, is common.
However, liver resection is appropriate for metastatic disease.499 In
addition to surgical resection, octreotide produces an improvement
of skin rash in up to 90% of patients and complete disappearance of
rash in 30% with symptomatic control of glucagon hypersecretion.500
Chemotherapeutic agents may have some activity (see later). The
tyrosine kinase inhibitor sunitinib has shown good efficacy in one
clinical trial, with prolongation of survival for up to 11.4 months.445
In spite of the overwhelming malignant presentation of these tumors,
the overall 5-year survival rate of 50% without resection is quite
encouraging and is likely due to slow progression.501
Somatostatinoma
Somatostatin first was identified in pituitary cells, and a role in the
regulation of growth hormone secretion was ascribed to it. Subsequently,
it was recognized as a hormone of the islet δ-cells. Somatostatin may
serve as a paracrine regulator of other pancreatic islet cell hormones.
Inhibition of secretion of those hormones may account for some of
the signs of somatostatinoma, such as diabetes, diarrhea, or gallbladder
disorders.502
Somatostatinoma occurs most frequently in the head of the pancreas,
and as many as 80% of patients have evidence of metastases at diagnosis.
The mean age at presentation is 55 years.503 Between 70% and 92%
of somatostatinomas are metastatic at presentation.504 Somatostatinomas
produce such common symptoms as diabetes (type 2–like diabetes
mellitus) and gallbladder disease; therefore the clinician usually does
not consider the diagnosis of somatostatinoma until late in the disease,
by which time metastases are likely. Surgical resection usually is not
curative.502 Because of the relatively mild hormonally induced symptoms
produced by somatostatin, octreotide does not have the same palliative
benefit it has in other pNETs. However, somatostatin analogues are
considered the first line of treatment of unresectable tumors.505
Cytoreductive surgery and chemotherapy may be the most appropriate
palliative strategies. The overall 5-year survival rate is 75%.506 Metastatic
disease is associated with 5-year survival of 60%.
Gastrinoma
Gastrin, the polypeptide hormone normally secreted by the G cell of
the gastric antrum, stimulates gastric acid secretion. Tumors of the
pancreatic or duodenal wall G cells are responsible for the signs and
symptoms of Zollinger-Ellison syndrome, a disorder characterized by
hypersecretion of gastrin. First described in 1955, this syndrome is
characterized by hypersecretion of gastric acid, severe peptic ulcer
disease, and an islet cell tumor of the pancreas. It is estimated that
less than 0.1% of patients with peptic ulcer disease have Zollinger-
Ellison syndrome.326 Eighty percent of gastrinomas are sporadic, and
the rest occur in association with MEN1.507
The hallmark of the gastrinoma syndrome is recurrent peptic ulcer
disease in spite of adequate medical or surgical treatment. Intermittent
diarrhea, often with steatorrhea, may be present as a result of digestive
enzyme inactivation in the small intestine by unbuffered gastric acid.
All manifestations of the Zollinger-Ellison syndrome are secondary
to hypersecretion of gastric acid. A history of MEN1 syndrome has
great significance, and gastrinoma may be present in up to 50% of
these patients.508 The combination of high gastric acid secretion and
hypergastrinemia is strongly suggestive of gastrinoma, but this combina-
tion also can occur in patients with retained gastric antrum after
surgery for peptic ulcer (antrectomy and Billroth II gastric resection)
and after gastric outlet obstruction. Gastric rugal hypertrophy, multiple
ulcers, or ulceration of the small bowel on radiographic studies suggests
gastrinoma.509
In a review of 60 patients treated surgically for gastrinoma at Ohio
State University, Ellison and associates reported that the incidence of
MEN was 27%, and a primary tumor was detected in nearly 90% of
cases. Twenty-five percent of gastrinomas can occur in the pancreas.
Extrapancreatic locations include the duodenum, predominantly the
first part of the duodenum, and the stomach, retroperitoneal lymph
nodes, liver, and bile duct.489,510 More than one-third of patients in
the Ohio State series had multiple tumors; metastatic disease in the
liver was identified in 20% of patients.511
The clinical diagnosis of Zollinger-Ellison syndrome has changed.
Although the original case reports stressed the appearance of extensive
and multiple gastric ulcers, a heightened index of suspicion and early
detection have altered this pattern of disease presentation. Suspicion
should be raised in any patient with peptic ulcer disease refractory to
Helicobacter pylori eradication. Classically, the diagnosis of Zollinger-
Ellison syndrome is based on four steps. The first step is to identify
fasting hypergastrinemia in association with a basal acid output greater
than 15 mEq/h. In general, a gastrin level greater than 10 times the
upper limit of normal (1000 pg/mL) in the presence of gastric PH
below 2 is pathognomonic. Less-convincing elevations in fasting serum
gastrin can be further evaluated with the secretin test, in which a peak
level of serum gastrin higher than 200 pg/mL over the baseline after
administration of secretin is considered diagnostic.508,512 A calcium
test was recommended after a prospective study as a second-line test
in patients in whom suspicion of gastrinoma is high but the result of
secretin test is negative.513 The remaining three steps include documenta-
tion of peptic ulcer disease (usually with endoscopy), localization of
the primary tumor, and assessment of malignancy. Approximately
75% of patients with Zollinger-Ellison syndrome have solitary ulcers
smaller than 1 cm in the first part of the duodenum, 14% in the
distal part, and 11% in the jejunum.514 Important to note, widespread
use of PPIs makes biochemical diagnosis of gastrinoma more chal-
lenging, because PPIs raise both gastrin levels and CgA levels. A fasting
specimen, off PPI therapy for 10 to 14 days, is ideal but should not
be considered in the setting of uncontrolled peptic ulcer disease with
bleeding.515
Localization of gastrinomas has been discussed extensively. Tech-
niques such as endoscopic ultrasonography, CT scan, MRI, selective
venous sampling for gastrin, and abdominal arteriography all have a
role in the diagnosis and management of this disease. As in other
NETs, octreotide scanning is useful for identifying primary and
metastatic lesions.516 Because gastrinomas are so frequently metastatic,
it is necessary to use every diagnostic modality to rule out metastatic
disease before planning surgery. If no metastatic disease is identified,
potentially curable operative intervention is indicated.517,518

Medical management in gastrinoma is directed toward the hyper-
secretion of gastric acid. Before the introduction of histamine receptor
antagonists, the only practical way to treat recurrent duodenal and
jejunal ulcers was total gastrectomy. PPIs may completely eradicate
symptoms of peptic ulcer disease caused by acid hypersecretion. Two
series using PPIs illustrated that symptomatic relief can be achieved in
more than 90% of patients with PPIs alone, with safe escalation of PPI
doses titrated to achieve gastric acid levels of less than 10 mEq/h.519,520
Higher doses are necessary initially but can be titrated down steadily
over time as patients tolerate the PPI. In refractory cases, octreotide
may be considered. Octreotide can be used if PPIs are unable to control
gastric acid secretion. Surgical resection of sporadic gastrinomas with
no evidence of metastatic disease is associated with a 50% to 97%
long-term survival rate.521,522,522a
Tumors Secreting Vasoactive Intestinal Peptide
In 1958, Verner and Morrison described a syndrome of watery diarrhea,
hypokalemia, hypochlorhydria, and metabolic acidosis (WDHA
syndrome), which is caused by high circulating levels of VIP secreted
by a pNET (VIPoma).523 Most studies of VIP infusions in healthy
volunteers have supported the concept that the diarrhea in VIPoma
patients may be caused directly by elevated circulating levels of vasoactive
intestinal polypeptide.524 Because most patients with this syndrome
have metastatic disease at presentation, usually to the liver, management
is mainly medical, with chemotherapy or a somatostatin analogue.
Surgical resection is rarely curative. As with carcinoid tumors and
other islet cell tumors, however, in patients with locally unresectable
disease or those with hepatic metastases, surgical cytoreduction or
regional therapy may improve symptom control. These tumors are
exceedingly rare and are associated with metastases in the chest or
retroperitoneum.525
Therapy
Radiation Therapy
Radiotherapy has similar indications as carcinoid tumors for symp-
tomatic lesions, particularly in the late and rare complication of bony
metastatic disease. Among patients who are not candidates for surgical
resection, some data from case reports and small case series indicate
that radiation therapy can produce symptomatic improvement and
freedom from local progression.526,527
Liver-Directed Therapy
As with carcinoid tumor, islet cell tumors often result in predominantly
hepatic metastases, and reduction in tumor bulk in the liver may
significantly influence hormone production and quality of life. For
that reason, resection of hepatic metastases is warranted in selected
patients. Endocrine and tumor response to hepatic arterial occlu-
sion, with or without chemotherapy, can be impressive. The Mayo
Clinic experience documented 46 patients with islet cell tumor
regression rates of 43% with hepatic artery occlusion alone versus
78.1% when chemotherapy was included. In the MD Anderson
series, 54 patients had pNETs, with a response rate of 35.2%, a
median PFS of 16.1 months, and a median overall survival of
23.2 months.439
Somatostatin Analogue
The somatostatin analogue octreotide is as useful in the treatment
of syndromes associated with ectopic hormone production in islet
cell tumors as it is in treatment of carcinoid tumors. In a series from
the Mayo Clinic, 24 patients with islet cell tumor were treated. The
response to somatostatin analogue was prompt, and symptoms were
palliated. However, the median duration of response was only 2.5
months, with only 2 of 24 patients (8%) continuing to benefit beyond
1 year.528 In another review of 66 patients treated with octreotide,
only 8 patients (12%) showed any indication of objective tumor
response.483 However, lanreotide was associated with significant
Cancer of the Endocrine System  •  CHAPTER 68 1103
prolonged PFS among patients with metastatic enteropancreatic
NETs of grade 1 or 2 in a double-blind placebo-randomized trial.423
The short duration of response and low incidence of objective tumor
regression suggest that somatostatin analogues in the treatment of
metastatic islet cell tumors have a more limited role than in other GI
carcinoid tumors.
Interferon
As with carcinoid tumors, interferon has historical significance in the
treatment of pNETs. Swedish investigators reported on 22 patients
treated with human leukocyte interferon, with an objective response
rate of 77% and a median duration of response of 8.5 months.432
Most of these responses were documented by decreased hormone
production rather than radiographic response. Clinical trials still
investigate the use of interferon, particularly in pegylated form, but
its use outside of clinical trials is not recommended.529
Chemotherapy
Cytotoxic chemotherapy for pNET is not a first choice for therapy.
Chemotherapy usually is attempted in patients with symptoms caused
by tumor bulk that may not be palliated by cytoreductive surgery
or in patients with uncontrolled syndromes of hormone excess. In
contrast to carcinoid tumors, pNETs generally are more responsive
to chemotherapy. The first chemotherapeutic drug to elicit significant
attention in the treatment of pNET was the antitumor antibiotic
streptozotocin. This drug has a diabetogenic action in some animals
that is correlated with selective uptake of the drug by pancreatic
β-cells.530 An ECOG study from 1980 compared streptozotocin alone
and streptozotocin plus 5-FU in advanced islet cell carcinomas.531 The
combination was superior to streptozotocin alone in overall rate of
response (63% versus 36%). These responses generally were of long
duration and yielded meaningful improvements in performance status
and symptoms, but were not reproduced in later studies in which more
standardized radiographic response criteria were used.532 More recent
studies in the RECIST era have demonstrated response rates of 39%
to 53% with streptozocin-based therapy, combined with either 5-FU
or doxorubicin or both.533–535 The combined results of two phase II
trials, although both studies have not met their primary end point,
demonstrated radiologic response and prolonged disease stability in
pNETs treated with oxaliplatin-fluoropyrimidine chemotherapy plus
bevacizumab.536
Dacarbazine (DTIC) has shown efficacy in pNET, and in newer
studies has been replaced by orally available temozolomide. Combina-
tions of temozolomide plus thalidomide, or temozolomide plus
capecitabine have demonstrated promising results in phase II studies,
with radiographic response rates as high as 70%.537,538 This combination
offers a possible cytotoxic combination for further study.
Targeted Therapy
Inhibition of the mTOR pathway demonstrated potential efficacy in
survival prolongation in preclinical and early phase studies, even without
frequent radiographic responses.445 In the phase III RADIANT-3 study,
everolimus (10 mg/day) was compared with placebo and demonstrated
an improvement in PFS from 4.6 months to 11.0 months, with 34%
of patients alive without progression at 18 months of therapy. This
result was achieved with the modest radiographic response rate of 5%
(2% for placebo).445 Patients were allowed to cross over at progression,
which may have confounded the overall survival data, but the improve-
ment in PFS is compelling for everolimus. In preliminary report from
a phase II trial that enrolled 150 patients with locally advanced or
metastatic pNETs, everolimus alone or in combination with bevaci-
zumab, the combination group was associated with a significantly
higher response rate (31% versus 12%) and superior PFS (16.7%
versus 14%).539
At the same time, sunitinib has been used in pNET with some
success in clinical trials. In phase II studies, a response rate of 17%
with a significant rate of disease stabilization was identified, prompting
1104 Part III: Specific Malignancies
a move toward phase III studies.450 The findings of the phase III
study were published in 2011 and demonstrated an improvement in
PFS from 5.5 months with placebo to 11.4 months with sunitinib.
Similarly, the objective response rate was low (9%), and overall
survival data may be confounded because of early stoppage of the
trial.449 A phase III trial demonstrated improved PFS with sunitinib
compared with placebo (11.4 versus 5.5 months).449 The develop-
ment of these two new compounds with significant improvement
in PFS marks a breakthrough in medical therapy for pNET. These
therapies may usher in a new era of therapy for metastatic NET, as
two well-tolerated, orally available compounds have been proven to
prolong PFS.
PARATHYROID CARCINOMA
Incidence
Parathyroid carcinoma is a malignant growth of parathyroid chief
cells. Severe hyperparathyroidism is the most common form of presenta-
tion and it represents less than 1% of patients with primary hyper-
parathyroidism.540,541 It is one of the rarest cancers, with an estimated
prevalence of 0.005%.540,542,543 Histologically, abnormal parathyroid
glands from patients with hyperparathyroidism have been characterized
as being hyperplastic, adenomatous, or malignant. Single-gland
involvement (“adenoma”) occurs in approximately 80% of patients
with hyperparathyroidism, and multiple-gland involvement (“hyper-
plasia”) in approximately 20%. Less than 2% of hyperfunctioning
parathyroid glands are malignant. The SEER cancer registry data
identified 224 patients with parathyroid carcinoma between 1998
and 2003 in the United States.7 During this time period, the incidence
of parathyroid carcinoma increased from 3.58 to 5.73 per 10 million
people. An incidence rate of 0.36 between 2000 and 2012 was reported
in a SEER registry recent publication.544 Whereas benign hyperpara-
thyroidism is more common in women (3 : 1), the incidence of
parathyroid carcinoma is equal between the two sexes. The age of
diagnosis is reportedly between 44 and 54 years.7
Etiology
As in many other cancers, a single-cell mutational event is believed
to give rise to parathyroid neoplasms. Whereas monoclonal tumors
likely result from somatic mutations in one parent cell (adenoma and
carcinoma), polyclonal expansion is thought to develop when multiple
original cells (hyperplasia) respond to an exogenous or endogenous
stimulus. Thus, monoclonal parathyroid carcinomas are likely caused
by single-cell derangement from mutation in either growth-promoting
or growth-regulating genes.
Studies have demonstrated that a subset of parathyroid adenomas
harbor a specific rearrangement of chromosome 11—inv(11)
(p15;q13)—a pericentromeric inversion that positions the PTH gene’s
5′ regulatory region upstream of the cyclin D1 gene, thereby driving
overexpression of cyclin D1 with the consequent growth promotion.545
As for tumor suppressor genes in parathyroid carcinoma, chromosome
1q25 harvests HRPT2 (hereditary hyperparathyroidism type 2) gene,
a gene responsible for growth control. Inactivating mutation(s) of this
tumor suppressor gene (also called cell division cycle 73 [CDC73])
has been recognized to play a central role in the molecular pathogenesis
of many parathyroid carcinomas. HRPT2 encodes parafibromin, a
protein whose function appears to involve regulation of gene expression
and inhibition of cell proliferation. Inactivated germline mutations
in the HRPT2 gene are responsible for an autosomal dominant type
of familial hyperparathyroidism, the hyperparathyroidism–jaw tumor
syndrome (HPT-JT).546 Patients with HPT-JT are predisposed to
develop ossifying fibromas of the jaw, cystic and neoplastic renal lesions,
uterine tumors, and parathyroid neoplasia with an increased risk of
parathyroid carcinoma (15%). In HPT-JT all parathyroid glands are
at risk for tumor development, but the tumors can occur asynchronously
over many years. Sporadic (nonfamilial) parathyroid carcinomas
frequently carry HRPT2 mutations, too. In two different studies,
HRPT2 mutations were reported to occur in 10 of 15547 and in 4 of
4 sporadic parathyroid carcinomas.548 Most mutations were somatic
as opposed to germline in HPT-JT. Unsuspected germline mutations,
however, were also discovered in a minority of patients with clinical
presentation of sporadic disease, suggesting that some of these individu-
als may have phenotypic variants of HPT-JT.548 The recognition that
family members of some patients with apparently sporadic parathyroid
carcinomas are also at risk for parathyroid malignancy has created a
new indication for genetic testing (see section on genetic counseling,
later). An obvious question is how prevalent are inactivating mutations
of parafibromin in benign parathyroid adenomas. In the largest series
of sporadic benign parathyroid adenomas reported to date, no mutations
of the HRPT2 gene could be detected.549 However, prevalence of
HRPT2 mutation was reported as 1.8% in two different studies.546,550
Other genes, through somatic mutation, also appear to participate in
the pathogenesis of parathyroid carcinoma. As examples, evidence has
implicated abnormal expression of the retinoblastoma and p53 pro-
teins.551,552 In another report, somatic mutations in the MEN1 gene
were found in 3 of 23 sporadic parathyroid carcinoma cases,553 although
diagnostic criteria for carcinoma in this study differed from other
studies in not requiring local invasion or metastases. No such mutations
had previously been reported in parathyroid carcinoma. Furthermore,
parathyroid carcinoma is not considered to be part of the MEN1-
associated phenotype. In a series of 348 cases of MEN1, only one
case (0.28%) of parathyroid carcinoma was reported.554
Clinical Characteristics
Symptoms of parathyroid carcinoma are primarily caused by high
levels of calcium in serum (hypercalcemia). Summarized from four
studies,547,555,556 they include:
• Constitutional symptoms (32%–74%):
• Muscle weakness, fatigue
• Nausea, vomiting, anorexia, constipation
• Increased thirst, frequent urination
• Bone pain, fractures (34%–73%)
• Neck mass (34%–52%)
• Kidney stones (32%–70%)
• Pancreatitis (0%–15%)
• No symptoms (2%–7%)
Signs of parathyroid carcinoma are also a consequence of hyper-
parathyroidism, as follows:
• Elevated serum calcium (14.6–15.9 mg/dL; >14 mg/dL in 70%)
• Elevated serum PTH (commonly 10-fold higher than the upper
limit of normal)
Although most patients with parathyroid carcinoma have hyper-
calcemia, a few patients are normocalcemic with a neck mass. In
contrast to benign parathyroid adenomas, 40% to 70% of parathyroid
cancers are palpable on physical examination.542,556,557 Nonfunctioning
parathyroid carcinomas are extremely rare, with fewer than 20 cases
reported.558,559 In contrast to patients with functional parathyroid
carcinomas, patients with nonfunctional tumors die from mass effect
and tumor burden, rather than from hypercalcemia.558 Multiglandular
(still monoclonal) parathyroid carcinoma is also extremely rare.560
Lymph node metastases have been observed in up to one-third of
patients with parathyroid carcinoma. Another one-third of patients
have metastasis to other sites, including lung, liver, and bone.561
Diagnosis
Because the clinical and biochemical presentation of hyperparathyroid-
ism is common to benign and malignant diseases, diagnosis of para-
thyroid carcinoma is usually established after the first surgery. Ideally,

preoperative confirmation or suspicion for parathyroid carcinoma would
lead to more aggressive surgical excision and therefore a higher cure
rate at the time of first surgery. A high index of suspicious should
exist in patients with marked hypercalcemia (serum calcium ≥14 mg/
dL), very high PTH (3–10 times above the upper limit of normal for
the assay), or profound hypercalcemic symptoms with simultaneous
manifestations of renal and bone involvement.557,562,563 For localization
purposes, patients should undergo a special radioactive scan of the
parathyroid glands (technetium-99m sestamibi scan). A neck ultrasound
examination with or without FNA washout for PTH measurement
may also help in localizing parathyroid tumors. Sonographic features
that suggest parathyroid carcinoma include heterogeneous or lobulated
lesions and large size.564,565 These tests are done to confirm which
parathyroid gland is abnormal but do not discriminate benign from
malignant disease. Because of the difficulty in diagnosing these tumors,
they usually are at a more advanced stage at presentation.558,566
Other diagnostic imaging modalities that could be beneficial for
disease localization and metastatic or recurrent disease include selective
venous sampling, CT scan, and MRI, with sensitivity of 83%, 93%,
and 69%, respectively.542
Owing to difficulty in differentiating benign from malignant disease
and the possibility of tumor rupture and seeding, FNA is not recom-
mended in preoperative diagnosis of parathyroid carcinoma.567
Once the specimen has been removed, pathologic examination
should be done to determine malignancy. The histopathologic examina-
tion of parathyroid carcinoma may show uniform sheets of cells arranged
in a lobular pattern separated by dense fibrous trabeculae, mitotic
figures in the tumor cells, and capsular and blood vessel invasion.568,569
However, these features have been noted occasionally in parathyroid
adenomas. Gross invasion beyond the capsule, including extracapsular
invasion, appears to correlate best with subsequent tumor recurrence.
Thus, because of the nonspecific nature of these histologic features,
the two criteria with which a definitive diagnosis of parathyroid
carcinoma can be made are:
• Local invasion of contiguous structures and/or
• Lymph node or distant metastases
In some cases, it may not be possible to differentiate parathyroid
adenoma from carcinoma at the time of diagnosis or initial surgery.
Local recurrence or the occurrence of distal metastases at subsequent
follow-up ultimately determines the correct pathologic diagnosis.
Some authors have suggested a benefit of immunohistochemical
panels that include parafibromin, galactin-3, PGD9.5, and Ki-67 in
diagnosing parathyroid carcinoma, with a sensitivity of 80% and
specificity of 100%.570
The HPRT2 gene is inactive in approximately 67% of sporadic
parathyroid cancers.547 However, there is no single molecular marker
that can distinguish between parathyroid carcinoma and adenoma.571
Some literature has suggested that an inverted third-generation to
second-generation PTH ratio is a tumor marker that could dif-
ferentiate patients with parathyroid carcinomas among patients
with primary hyperparathyroidism, with sensitivity of 78.5% and
specificity of 98.9%.572–575
Treatment
Surgical Therapy
Total parathyroidectomy or en bloc resection of the parathyroid mass
with negative margins and any adjacent tissues that have been invaded
by tumor is currently the treatment of choice.576 In the SEER registry,
78.6% of patients underwent total parathyroidectomy and 12.5%
underwent en bloc resection.7 En bloc resection could include the
ipsilateral thyroid lobe, paratracheal alveolar and lymphatic tissue, the
thymus, or some of the neck muscles, and in some advanced cases
the recurrent laryngeal nerve.555,556,577 Some surgeons recommend
ipsilateral lymph node dissection.578 Because parathyroid carcinoma
can be seeded locally from the primary tumor, it is important to avoid
Cancer of the Endocrine System  •  CHAPTER 68 1105
capsular disruption and tumor spillage during surgery. If the diagnosis
of parathyroid carcinoma is made postoperatively, several authors
recommend reoperation with ipsilateral thyroidectomy,579 but a survival
benefit has not been clearly demonstrated.561,580 If during surgery, a
parathyroid tumor appears to be well demarcated (not invading sur-
rounding tissue) but is later found on pathologic examination to have
invaded adjacent tissue, reoperation to remove all tumor tissue is
recommended. After surgical resection, recurrence rates of up to 49%
to 60% have been reported.541,542,556,561,580
Surgical complications such as hematoma, recurrent laryngeal nerve
injury, injury to surrounding structures, and postoperative metabolic
complications including hypocalcemia and hypophosphatemia have
been reported, with a perioperative mortality rate of 1.8%.542,563,580
The postoperative management of patients with parathyroid carcinoma
should include close monitoring of the patient’s serum calcium
concentration. Patients with parathyroid carcinoma are especially at
risk of developing “hungry bone syndrome” and therefore need to be
preventively treated with large doses of calcium and calcitriol. Patients
with recurrent or metastatic parathyroid carcinoma can be treated
surgically. Resection of lesions in the neck, lungs, and liver will often
result in significant palliation of hypercalcemia.542
Medical Therapy
The following treatments may be used to correct hypercalcemia caused
by parathyroid carcinoma preoperatively and when the condition is
no longer amenable to surgery:
• Drugs that acutely lower serum calcium level (e.g., gallium nitrate),
calcitonin (hypocalcemic hormone), and hydration (intravenous
fluids) and loop diuretics can be used as first-line treatments.
• Calcimimetics are drugs that reduce PTH secretion by producing
allosteric changes in the calcium-sensing receptor that induce signal-
ing without the need of calcium or at lower thresholds.581 Cinacalcet,
a longer-acting calcimimetic drug, is used for the treatment of
secondary hyperparathyroidism associated with renal failure and
hypercalcemia associated with parathyroid carcinoma. In a 16-week
open-label study of 29 patients with inoperable parathyroid carci-
noma, cinacalcet (dose titrated to achieve calcium ≤10 mg/dL or
up to 90 mg four times daily) successfully reduced serum calcium
concentration by at least 1 mg/dL in 62% of patients.581 Mean
PTH levels decreased but not significantly. Adverse events (nausea,
vomiting, headache, dehydration) were common and resulted in
discontinuation in five patients.
• The bisphosphonate pamidronate has been reported to improve
hypercalcemia in individual cases of parathyroid carcinoma.582 A
similar response was reported for zoledronic acid, which is more
potent than pamidronate in treating hypercalcemia of malignancy.583
• Denosumab, an osteoblast inhibitor that binds to the receptor
activator of nuclear factor–κB ligand (RANKL), has been suc-
cessfully used to treat refractory hypercalcemia in some case
reports.584–587
Adjuvant Therapy
Both adjuvant chemotherapy and radiation therapy have had generally
poor results for the treatment of parathyroid carcinoma. Use of either
should be considered as a last resource—only when a patient is a poor
candidate for surgery and/or hypercalcemia cannot be controlled.
Radiation therapy experience is limited to small observational
studies. In a series of 26 patients with locally invasive disease followed
for a mean of 7.9 years (range, 2 to 21 years), only 1 of 6 patients
receiving adjuvant radiation therapy had a local relapse, compared
with 10 of 20 who had not received radiation therapy.561
Chemotherapy has been tried whenever other treatment modalities
have failed. Various agents, alone or in combination, have resulted in
occasional responses. An example of one patient with pulmonary
metastases responding to treatment with dacarbazine, 5-FU, and
cyclophosphamide with normalization of serum calcium for 13 months
1106 Part III: Specific Malignancies

has been reported, but there are no randomized controlled trials assessing
the efficacy of these agents.563
Biologic agents based on gene products such as recombinant
parafibromin, an inhibitor of cell proliferation in parathyroid neoplasia,
telomerase inhibitors such as azidothymidine, and immune therapy
constitute novel emerging therapies with encouraging in vitro results
and may prove useful clinically in the future.576
Radiofrequency ablation of metastatic disease with unresectable
disseminated lesions has been reported, sometimes in combination
with transcatheter arterial embolization.588,589
Finally, in metastatic parathyroid carcinoma with hypercalcemia,
immunotherapy with PTH-like immunogenic fragments for PTH
antibody production has shown some promising results in terms of
improving hypercalcemia and quality of life.572,590,591
Genetic Counseling
Genetic HRPT2 testing is indicated when features suggestive of HPT-JT
are present in the index patient. Genetic diagnosis of a germline
HRPT2 inactivating mutation indicates that such a patient may have
classic HPT-JT, expressing its initial manifestation, or phenotypic
variants, such as familial isolated hyperparathyroidism, or a form of
HPT-JT with altered penetrance. A subset of patients with sporadic
parathyroid carcinoma have been found to have germline HRPT2
mutations,547 and such mutations carry important implications for
management of the patient and/or for early detection and prevention
of parathyroid malignancy in family members. A negative test result,
however, is a challenging situation because among families with classic
HPT-JT, 40% have no detectable mutation.550,592 There is no consensus
regarding surveillance in these families. Thus, genetic testing for
germline HRPT2 mutation is clinically appropriate in most patients
with sporadic parathyroid carcinoma.
Outcomes
Parathyroid carcinomas grow slowly in most patients but can occasion-
ally be aggressive. The disease typically seems to follow one of three
courses: one-third of patients are cured at initial or follow-up surgery;
one-third develop recurrence after a prolonged disease-free period but
may be cured with reoperation; and one-third of patients experience
a short and aggressive course.542 Survival, however, may be improving.
The National Cancer Database survey (1985–1995) reported 5- and
10-year survival rates of 55.5% and 49%, respectively, in a series of
286 patients.593 In a study using the SEER cancer registry (1988–2003),
5- and 10-year survival rates were 83.9% and 67.8%, respectively.543
These survival rates are consistent with a 2016 report from the SEER
cancer registry, with a 5-year survival rate of 82.5% and a 10-year
survival rate of 64.8%.544 The recurrence rate is 50% or greater among
patients with lymph node or distant metastasis, with a mean time of
recurrence ranging between 2.5 and 4.8 years.561,580 In functioning
parathyroid carcinoma, recurrence usually manifests as elevated serum
calcium and/or PTH. Young age, female sex, recent year of diagnosis,
and absence of distant metastases were associated with improved
survival.
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