Parathyroid Pathology

Hyperparathyroidism and Parathyroid Tumors

Diane Carlson, MD

Context.Primary hyperparathyroidism is the most

common cause of hypercalcemia in the outpatient
setting. Parathyroid adenomas are common, unlike
other parathyroid tumors. This review presents a
brief summary of current updates in parathyroid
pathology.
Objective.To review parathyroid development and
discuss issues in hyperparathyroidism and diagnosis of
parathyroid lesions, including the application of immunohistochemistry and molecular biology.
Data Sources.Current texts, PubMed (National Library
of Medicine) articles, and Memorial Sloan-Kettering
Cancer Center archives.

Conclusions.Primary hyperparathyroidism is most commonly seen with sporadic adenomas, followed by hyperplasia,
multiple adenomas, and carcinoma. Autosomal dominant
familial hyperparathyroidism syndromes should be considered in the evaluation of patients with parathyroid lesions,
particularly in association with parathyroid carcinoma. While
the incidence of parathyroid carcinoma is quite low, it is seen
with a greater frequency in those patients with hyperparathyroidism-jaw tumor syndrome. Inactivation of the tumor
suppressor gene HRPT2 can be identified in a large number
of parathyroid carcinomas. Hence, germline HRPT2 gene
mutations may reflect unrecognized syndromic patients.
(Arch Pathol Lab Med. 2010;134:16391644)

HISTORICAL BACKGROUND
In 1849 Sir Richard Owen performed an autopsy on a
rhinoceros and gave the first description of the parathyroid gland. He described it as a small compact yellow
glandular body which was attached to the thyroid at the
point where the veins emerged. 1
The first description of the parathyroid glands in
human beings was given by Ivar Sandstrom, a medical
student in Uppsala, Sweden in 1880.1,2 He suggested that
these glands be named the glandulae parathyroideae.1,2 The
function of these structures was unknown at that time. In
1926, at the Massachusetts General Hospital in Boston,
Edward Churchill, assisted by an intern named Oliver
Cope, operated for the seventh time on the famous sea
captain Charles Martell for severe primary hyperparathyroidism (HPT).1 An ectopic adenoma was found substernally. Although the operation was successful, Captain
Martell died 6 weeks postoperatively, most likely from
laryngeal spasm, during a procedure to relieve ureteral
obstruction secondary to stones. Ironically, 83 years later,
ectopic parathyroid glands continue to be a diagnostic
surgical challenge.

EMBRYOGENESIS
While there are generally 4 parathyroid glands, weighing 30 to 40 mg each, autopsy studies have shown that 2%
to 13% of healthy individuals have supernumerary
parathyroid glands, most commonly with a fifth gland
located in the cervical thymus.3 Approximately 1% to 3%
of people have only 3 identifiable glands and 0.6% have 6
parathyroid glands.4 Rare reports of the presence of 7 and
up to 12 parathyroid glands have been described in the
literature.36 The presence of ectopic parathyroid tissue has
been attributed to abnormal migration during embryogenesis. During development, at day 26, five pairs of
pharyngeal pouches form. The superior parathyroids
develop from the fourth pharyngeal pouch and the
inferior from the third. The inferior parathyroids migrate
a greater distance, and do so in conjunction with thymic
tissue. Therefore, these are more likely to be found in
ectopic sites. The main blood supply is the inferior thyroid
artery, as well as the superior thyroid artery, directly from
thyroid.

Accepted for publication February 24, 2010.

From the Department of Pathology, Memorial Sloan-Kettering Cancer
Center, New York, New York. Dr Carlson is now with the Department of
Pathology, Cleveland Clinic Florida, Weston, Florida.
The author has no relevant financial interest in the products or
companies described in this article.
Presented in part at the Surgical Pathology of Neoplastic Diseases
course, Memorial Sloan-Kettering Cancer Center, New York, New York,
May 1822, 2009.
Reprints: Diane Carlson, MD, Department of Pathology, Cleveland
Clinic Florida, 3100 Weston Blvd, Weston, FL 33331 (e-mail: carlsod@
ccf.org).
Arch Pathol Lab MedVol 134, November 2010

ANATOMY OF THE PARATHYROID GLANDS

The parathyroid glands are small (36 mm), brown,
round to ovoid soft structures, which may be somewhat
flattened or bilobed. Histologically, each gland has a thin
fibrous capsule that overlies an arborizing network of
adipose tissue, blood vessels, and glandular parenchyma
(Figure 1). The amount of stromal fibroadipose tissue
increases from puberty and continues to do so until
around the fifth decade of life, accounting for approximately 50% of the gland volume.5 The adult parathyroid is
composed predominantly of chief cells, as well as
oxyphilic cells, which are mitochondria rich, and transiParathyroid Pathology and Parathyroid TumorsCarlson

1639

Figure 1. Normal parathyroid gland containing scattered fibroadipose tissue (hematoxylin-eosin, original magnification 320).
Figure 2. a, Actual frozen section of parathyroid adenoma demonstrates dilated follicular growth with eosinophilic colloidlike material. b, Frozen
section control of 2, a (hematoxylin-eosin, original magnifications 3100 [a and b]).
Figure 3. Oxyphilic (oncocytic) adenoma. Compressed rim of normal parathyroid adjacent to eosinophilic adenoma cells (hematoxylin-eosin,
original magnification 320).
Figure 4. a and b, Atypical adenoma in an 11-year-old boy with hyperparathyroidism-jaw tumor syndrome. While there is a uniform population of
cells without pleomorphism (a), a focus of tumor necrosis is present (b) (hematoxylin-eosin, original magnifications 3400 [a and b]).

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Arch Pathol Lab MedVol 134, November 2010

Parathyroid Pathology and Parathyroid TumorsCarlson

Table 1.

Lesions Which May Be Associated With

Hyperthyroidism

Table 2. Parathyroid-Containing Specimens at

Memorial Sloan-Kettering Cancer Center, 19992009
(n = 574)

Nonneoplastic parathyroid lesions

Parathyroid hyperplasia
Primary chief cell hyperplasia
Waterclear cell hyperplasia
Parathyroiditis
Parathyroidal cysts
Neoplasms of the parathyroid glands
Adenoma
Atypical adenoma
Lipoadenoma
Carcinoma
Secondary neoplasms
Metastases
Invasion of tumors by direct extension

tional oxyphilic cells, which appear to represent an

intermediate phase from chief cell to oxyphilic cell.
ISSUES IN HYPERPARATHYROIDISM
The level of parathyroid hormone (PTH) is inversely
proportional to the level of calcium in the blood, which is
tightly regulated between 8.8 and 10.2 mg/dL (to convert
to millimoles per liter, multiply by 0.25). Excessive
hypercalcemia leads to cessation of PTH production.
Primary hyperparathyroidism is characterized by the
autonomous production of parathyroid hormone resulting in hypercalcemia and is the most common cause of
hypercalcemia in the noninpatient setting, in people
without an underlying malignancy. The current incidence
of primary hyperparathyroidism has been reported as 17.7
cases per 1 000 000 persons in the United States.7 Hereditary disorders account for approximately 10% of cases of
hyperparathyroidism.8
Most commonly with primary hyperparathyroidism,
one sees sporadic adenomas (85%), followed by hyperplasia (10%), multiple adenomas (4%), and carcinoma
(1%)1,4,7,8 (Table 1). The incidence of parathyroid carcinoma is quite low. Of 574 specimens containing parathyroid
tissue and reviewed from 1999 to 2009 at Memorial SloanKettering Cancer Center (MSKCC), New York, New York,
there were 8 reported cases of hyperplasia, with 195
adenomas, 22 atypical adenomas, and 2 carcinomas; the
remaining cases consisted of parathyroid glands incidentally removed in part or in total with thyroid lobectomy or
thyroidectomy procedures (Table 2).
Historically, patients with hyperparathyroidism have
presented with symptoms including urolithiasis, bone
pain, and pathologic fractures and nonspecific symptoms
such as depression, lethargy, and vague aches and pains;
hence, Walter St Goars classic 1957 description of stones,
bones, and abdominal groans. Now, however, most
patients are asymptomatic and identified incidentally on
routine serology.1,7
Osteitis fibrosa cystica is a markedly rare disease,
present in only 2% of individuals diagnosed with primary
hyperparathyroidism, which accounts for 90% of instances of the disease.1 It is the excess of PTH, stimulating
osteoclastic bone resorption, which can lead to osteitis
fibrosa cystica (OFC; osteitis fibrosa; or von Recklinghausen disease of bone), a classic skeletal manifestation of
advanced hyperparathyroidism. There is a loss of bone
mass, with peritrabecular fibrosis and the formation of
cystlike brown tumors in and around the bone. Cysts may
Arch Pathol Lab MedVol 134, November 2010

Specimen

Adenoma
Atypical adenoma
Hyperplasia
Carcinoma
Benign, normocellulara

No. (%)

195
22
8
2
347

(33.9)
(3.8)
(1.3)
(0.35)
(60)

Parathyroid tissue representing portions of or total glands removed in

thyroid lobectomy or thyroidectomy procedures.

be lined by osteoclasts, often with abundant hemosiderin,

which led to their designation as brown tumors. These
tumors may preferentially affect mandible or maxilla, but
also have been known to arise in other craniofacial bones,
including temporal bone, nasal cavity, and the sinuses.
Aside from facial bone involvement, one may see rib and
pelvic bone involvement. The symptoms of the disease are
the consequences of both the general softening of the
bones and hypercalcemia, and include fractures, kidney
stones, nausea, anorexia, and weight loss. Before 1950,
around half of the patients diagnosed with hyperparathyroidism in the United States saw the disease progress to
OFC, but with early identification techniques and improved treatment methods, instances of OFC in developed
countries are increasingly rare. When treatment is
required, it normally involves addressing the underlying
hyperparathyroidism before the commencement of longterm treatment for OFCdepending on its cause and
severity, this can range from hydration and exercise to
surgical intervention. Disorders such as familial hyperparathyroidism, multiple endocrine neoplasia type 1
(MEN 1), and hyperparathyroidism-jaw tumor syndrome
can, if left unchecked, result in OFC.
Treatment of Primary Hyperparathyroidism
Intraoperative evaluation of the parathyroid gland can
be reliably performed with both touch preparation and/or
actual frozen section. Accuracy is high and very frequently a function of experience. Common pitfalls lie in the
observation of a predominant follicular pattern of growth
or oxyphil-predominant areas mimicking oncocytic thyroid parenchyma, be it neoplastic, hyperplastic, or
reactive. Follicles may even contain eosinophilic colloidlike secretions, further complicating the evaluation (Figure 2, a and b).
Generally, surgery is the mainstay of treatment of
primary hyperparathyroidism, particularly for the patient
younger than 50 years, the symptomatic patient, and those
who cannot be closely monitored medically.7 In the past,
exploration and intraoperative identification of all 4
parathyroid glands were performed. However, today,
with the advent of the preoperative technetium Tc 99m
sestamibi scan and intraoperative PTH assays, the
minimally invasive parathyroidectomy has evolved. The
sensitivity of these sestamibi scans for the detection of
adenomas is between 85% and 100%, with a high
specificity.7,9 While frozen section to obtain the weight of
the adenomatous gland is commonly performed at
MSKCC, and is a useful tool in the intraoperative
identification of parathyroid tissue, we rarely see removal
beyond the adenoma at the time of frozen section. Rather,
Parathyroid Pathology and Parathyroid TumorsCarlson

1641

it is the intraoperative decrease of PTH by 50% (or greater)

after removal of the questionable gland that is indicative
of hyperfunctioning tissue and, hence, correlates with
adenoma.4,9
PARATHYROID ADENOMA
Some studies4,5 have demonstrated that exposure to
ionizing radiation to the head and neck, in a dosedependent manner, increases the risk of developing
parathyroid adenomas. There is nearly a 4-fold increase
in parathyroid tumors among people who were exposed
to the atomic bomb in Hiroshima.4
Historically, the criteria for adenoma have generally
included a pushing border with an absence of intralesional fibroadipose tissue, complete circumscription with a
rim of normal parathyroid at the periphery, and an
absence of lobular growth. The current definition is no
longer purely histologic, but rather includes the effect of
gland removal, with intraoperative PTH decrease and
subsequent return to normocalcemia and long-term cure.
Rare double adenomas have also been described,
particularly in association with autosomal dominant
endocrine disorders.
While most adenomas are composed of chief cells, a
small percentage may be oxyphilic (.90% oxyphils) and
rare water-clear adenomas have also been described.
Interestingly, oxyphilic adenomas are apparently more
readily detected on sestamibi scans5 (Figure 3).
Lipoadenomas are another exceedingly uncommon
entity, with fewer than 50 reported cases. These were
initially thought to be hamartomatous lesions, paradoxically with an increase in stromal fat, but they have been
shown to be functional4,10; that is, these tumors have been
associated with hyperparathyroidism and their surgical
removal has led to normal PTH and calcium levels.
ATYPICAL ADENOMA
Akin to the identification of a malignant paraganglioma,
parathyroid carcinoma can be a difficult diagnosis to
reach. Hence, those tumors whose features are worrisome,
but not diagnostic of malignancy, fall under the rubric of
atypical adenoma. According to Seethala et al,4 the
presence of 2 or more of the following attributes will lead
to this diagnosis: incomplete invasion of the capsule,
fibrous bands, pronounced trabecular growth, mitotic
activity greater than 1 per 10 high-power fields, and tumor
necrosis (that is not fine-needle aspiration or infarct related)
(Figure 4, a and b). There is apparently debate as to
whether abnormal mitoses should be acceptable in the
diagnosis of atypical adenoma; their presence should
certainly lead to further investigation toward the elimination of malignancy.11
PARATHYROID CARCINOMA
Parathyroid carcinomas represent fewer than 4% of
cases of parathyroid disease.5 Preoperatively, the main
clinical finding in parathyroid carcinoma is high calcium
and PTH levels. More frequently, patients have symptomatic disease and can present in hypercalcemic crisis.1
Up to 75% of patients may present with a palpable neck
mass, and recurrent laryngeal nerve palsy should alert the
clinician to the possibility of malignancy.12,13 While the
presence of metastatic disease to regional lymph nodes or
distant sites can confirm the diagnosis preoperatively, the
diagnosis can be suggested intraoperatively on the basis of
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Arch Pathol Lab MedVol 134, November 2010

tumor invasion into surrounding structures. Intraoperative examination of frozen section to establish a definitive
diagnosis of carcinoma is somewhat controversial because
of the overall difficulty of rendering the diagnosis.
Histopathologic findings (in addition to those of atypical
adenoma) include a high mitotic rate and capsular,
vascular, or perineural invasion2,4,5,8 (Figure 5, a through
d). Other findings such as cellular pleomorphism and
atypia can also be seen, including atypical mitoses. These
abnormal mitotic figures do appear to be a unique
hallmark, though not pathognomic, of this entity. Mortality rates for parathyroid carcinomas, particularly for those
patients with recurrence within the first 2 years postoperatively, are high and reported to be between 46% and
65%.1214 The American Joint Committee on Cancer (AJCC)
neither has staged nor has planned staging for parathyroid carcinoma in the 7th edition of the AJCC Cancer
Staging Manual, because of the rarity of the condition.15
IMMUNOHISTOCHEMISTRY AND
MOLECULAR BIOLOGY
When confronted with the definitive identification of a
small fragment of tissue suspected to be parathyroid, an
antibody to parathyroid hormone may be the most useful,
straightforward, single antibody to use for immunohistochemistry analysis. The strong cytoplasmic staining of
PTH in chief cells is readily identifiable. Additionally,
various low-molecular-weight cytokeratins (CKs) (eg,
CK8, CK18, and CK19), and chromogranin A will be
immunoreactive.4,5,7,8,11 Adenomas, unlike normal parathyroid tissue, express neurofilament and will also label
for vimentin and glial fibrillary acidic protein.8 The
intensity of staining for PTH and chromogranin A has
been described as less intense in adenomas than in normal
and hyperplastic parathyroid tissue. Of note, both CD3
and CD4 have been shown to be immunoreactive with
normal and abnormal parathyroid glands; while not
necessarily of diagnostic utility, this is a valuable potential
pitfall of which to be aware.
Numerous ancillary immunohistochemical markers of
cell cycle and proliferation markers have been evaluated
in an attempt to define parathyroid neoplasia, including
MIB-1 (Ki-67), cyclin D1, p27kip1, Rb, bcl2, mdm2,
calcium-sensing receptor, and gelectin-3.11,1619 While
many of these are considered useful, none are definitive
nor diagnostic of adenoma or other pathologic entities.
Parathyroid adenomas have been shown to have rearrangements involving the PTH locus that map to 11p15.3
15.1.4,5,18,19 These genes encode a cyclin, parathyroid
adenomatosis 1, also known as cyclin D1. However, high
levels of cyclin D1 have been reported in carcinomas,
adenomas, and hyperplasia. Interestingly, TP53 overexpression has generally not been detected in parathyroid
neoplasms, suggesting that this tumor suppressor gene
does not play a role in parathyroid tumorigenesis. A
decrease in mdm2 expression has been seen in tumors
with adverse histologic features. It has been proposed by
some11 that p27+, bcl2+, Ki-672, mdm2+ is unique to
nonmalignant neoplasms.
All of the syndromes listed in Table 3 are inherited in an
autosomal dominant manner. The multiple endocrine
neoplasia (MEN) syndromes are characterized by the
hyperplastic or neoplastic proliferation of 1 or more
endocrine glands. With regard to the parathyroid glands,
these patients will have hyperplasia or multiple adenoParathyroid Pathology and Parathyroid TumorsCarlson

Figure 5. Parathyroid carcinoma. a, Trabecular pattern of growth. b, Widely infiltrative growth. c, Perineural invasion by parathyroid carcinoma.
d, Lymphovascular invasion (hematoxylin-eosin, original magnifications 3200 [a and c], 3100 [b], and 3400 [d]).

mas, the latter being more prone to recurrence or

persistence. Multiple endocrine neoplasia 1associated
hyperparathyroidism, although a multigland disease, is
oligoclonal, with a gene expression profile more similar to
adenomas. The mutated tumor suppressor gene MEN1
encodes a nuclear protein, menin, whose function it is to
interact with SMAD3 to suppress transforming growth
factor b.20 Parathyroid carcinoma has not been proved to
be a component of MEN 1. While nearly 90% of patients
with MEN 1 have hyperparathyroidism, only 20% to 30%
of patients with MEN 2A do so.
Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is
an inherited disorder with incomplete penetrance. The
disorder may be characterized by parathyroid adenoma or
carcinoma, benign fibro-osseous lesions of the mandible
or maxilla, and renal cysts or tumors. Approximately 80%

Table 3.

Familial Hyperparathyroidism Syndromes

MEN 1 (multiple endocrine neoplasia 1)

MEN 2A (multiple endocrine neoplasia 2A)
HPT-JT (hyperparathyroidism-jaw tumor syndrome)
FIHP (familial isolated hyperparathyroidism)
Arch Pathol Lab MedVol 134, November 2010

of patients have hyperparathyroidism and up to 15% of

these patients have parathyroid carcinoma. The HRPT2
gene (for hyperparathyroidism 2) is a putative tumor
suppressor gene that was identified and has been mapped
to 1q25q31.12,20 The gene encodes a protein named
parafibromin for its relationship to parathyroid disease
and fibro-osseous jaw lesions. While mutations predicted
to inactivate this protein were first described in patients
with HPT-JT syndrome, inactivating mutations of HRPT2
are found in nearly 70% of all parathyroid carcinomas.20 In
the familial (ie, autosomal dominant) cases, the mutation
is germline and in the sporadic cases, it has been shown to
be somatic. Up to 20% of patients with apparently
sporadic parathyroid carcinoma harbor germline HRPT2
mutations and therefore represent unrecognized syndromic patients.20 While HPT-JT syndrome is an exceedingly
uncommon entity, with an unknown incidence or prevalence, like MEN, it should be considered in the
differential diagnosis for the adolescent presenting with
hyperparathyroidism.
Familial isolated hyperparathyroidism is distinguished
by benign mutliglandular parathyroid disease and absence of extraparathyroidal disease; it is estimated to
represent 1% of cases of primary hyperparathyroidism.
Parathyroid Pathology and Parathyroid TumorsCarlson

1643

While the mutated gene is not identified in many cases,

there are kindreds in which either MEN1 or HRPT2 have
been identified. This disease entity has yet to be further
elucidated and better characterized.
CONCLUSIONS
Primary hyperparathyroidism is most commonly seen
with sporadic adenomas, followed by hyperplasia, multiple adenomas, and carcinoma. At Memorial SloanKettering Cancer Center, an oncologic tertiary care facility,
adenomas are seen with a lower frequency than that
generally reported in the literature. The distinction
between adenoma, atypical adenoma, and carcinoma can
be murky, and one may need to consider clinical findings
in addition to the histologic appearance. There is currently
no pathognomic immunophenotype to define neoplasia.
While the incidence of parathyroid carcinoma is quite low,
it is seen with a greater frequency in patients with
hyperparathyroidism-jaw tumor (HPT-JT) syndrome.
Hence, autosomal dominant familial hyperparathyroidism syndromes should be considered in the differential
diagnosis, particularly in association with parathyroid
carcinoma. Inactivation of the tumor suppressor gene
HRPT2 can be identified in a large number of parathyroid
carcinomas and therefore, germline HRPT2 gene mutations may reflect unrecognized syndromic patients.
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