Intraoperative Consultation in Head and Neck Pathology
Case 7 -
Bruce M. Wenig, M.D.
Mary S. Richardson, D.D.S., M.D.
A 51 year old man presented with increasing fatigue and a
palpable neck mass. Laboratory evaluation showed decrease renal function; serum calcium was normal.
FNAB was performed and diagnosed as "cellular proliferation with a microfollicular pattern of thyroid or
parathyroid origin". A neck exploration was subsequently performed
At the time of surgery a mass in the left neck was
excised. The surgeon noted that it was difficult to excise the mass due to its adherence to surrounding
structures, including the left lobe of the thyroid gland. The surgeon noted that there had been no
history of any prior surgical manipulation of the left neck. The specimen received included a round to
oval, firm mass that appeared encapsulated but adherent to a portion of resected thyroid gland. Due to
the presence of thyroid gland it was difficult to accurately assess the weight of the resected
parathyroid gland, but the approximate weight was 6.5 grams.
Representative portions of the specimen were taken for frozen section analysis.
At low magnification a cellular proliferation was
present showing a trabecular growth and focal areas of extracellular hyalinization. The latter in areas
was seen to course in between the cellular proliferation. No residual normal appearing parathyroid
parenchyma was seen. At higher magnification the neoplastic cells were composed of relatively uniform
round to oval, hyperchromatic nuclei lacking any significant pleomorphism. Rare mitotic figures were
present. There was no evidence of necrosis. Along the periphery of the lesion the neoplastic cells
infiltrated into adjacent connective tissue, including into skeletal muscle and around blood vessels.
Definitive evidence of lymph-vascular space or neurotropism was not identified. The tumor was adherent
to the thyroid parenchyma but did not nivade into the thyroid gland.
An en bloc resection to include the ipsilateral thyroid lobe and
modified neck dissection was performed.
Diagnosis on Permanent Section:
Parathyroid carcinoma; cervical lymph nodes were
negative for carcinoma.
Intraoperative Consultation of Parathyroid Proliferative Disease (PPD)/Hyperparathyroidism
Optimal management of primary hyperparathyroidism is achieved by selective removal of parathyroid
glands guided by the histologic findings in each gland. The surgical
management of a patient with primary hyperparathyroidism is to remove one or more enlarged parathyroid
glands. To this end the pathologist plays a primary role in the clinical care of the patient. At the
time of parathyroid exploration the initial assessment of the excised tissue is the intraoperative
histopathologic determination of whether the excised tissue is parathyroid tissue and, if so, whether it
is or is not abnormal. In the majority of cases the identification of parathyroid tissue is rather
simple. However, at times this determination may prove difficult. Further, it is well established that
the differentiation of an adenoma from hyperplasia in a single enlarged gland cannot be made by
histopathologic evaluation and that detailed clinical information (pre- and
postoperative) is required to arrive at the diagnosis.
The parathyroid glands are of endodermal origin and originate as symmetrical nodular epithelial
proliferations on the dorsal aspects of the third and fourth pharyngeal pouches around the fifth week of
gestation. The superior gland develops from the fourth pharyngeal pouch which is connected with the
pharynx. The fourth pharyngeal pouch is a complex bilobed structure composed of a ventral component, the
ultimobranchial body which fuses with the lateral aspect of the thyroid lobe, and a dorsal epithelial
proliferation which separates to become the superior thyroid gland, assuming the usual adult position
along the posteromedial aspect of the thyroid gland. The superior parathyroid glands tend to be more
contant in position than the inferior glands. The inferior parathyroid gland develops from the third
pharyngeal pouch, also a complex bilobed structure, associated with the thymus, from which it separates
after migrating caudally to a position near the lower pole of the thyroid gland.
The most common developmental "anomaly" of the parathyroid glands is ectopia, which usually
represents a variation in embryologic migratory pattern. Parathyroid agenesis is very rare. The
DiGeorge syndrome includes complete or partial absence of the third and fourth pharyngeal pouches and
their derivatives, including the thymus, the parathyroid glands and thyroid C cells. DiGeorge syndrome
manifests as multiple facial malformations, hypoplasia of the thyroid, hypoparathyroidism, and cardiac
There is considerable variation in the location of the parathyroid glands in adults, though their
distribution follows a predictable pattern based on their embryologic development. The superior glands
are more constantly placed than the inferior glands. The superior glands are located along the posterior
edge of the thyroid superior to the intersection between the recurrent laryngeal nerve and the inferior
thyroid artery. (approximately 80%). In a minority of instances (approximately 20%) the superior glands
are found posterior to the upper pole of the thyroid, where they may be intimately associated with the
thyroid capsule. The superior glands may rarely be retroesophageal or retropharyngeal, or even
The inferior parathyroid glands are more variably placed. Though the most common location is around
the posterolateral or inferior aspects of the lower pole of the thyroid gland (approximately 60%), they
may be found within the portion of the thymus that is adjacent to the lower pole of the thyroid. Since
the inferior glands pursue a lengthy developmental migratory course, they may be found from the level of
the hyoid bone to the mediastinum, where they may be situated in thymic tissue or in the pericardium.
Most individuals have at least four parathyroid glands; approximately 13% of the population have
supernumerary glands, ranging in number from 1 additional gland to as many as 12 glands in very rare
instances. Rare individuals with fewer than four glands have been reported; however, there is doubt in
at least some of the cases that all of the glands were identified. Supernumerary glands may be
well-formed (about half of the cases) or may be less distinct aggregate of parathyroid tissue located
near the normal glands.
Normal Size and Weight (Table 1)
The parathyroid glands are soft yellow-brown to dark brown, circumscribed ovoid structures. Some
parathyroid glands are bilobed or flattened. Each gland measures approximately 3 to 6 mm in length; the
combined weight increases from early infancy (mean, 5-9 mg) to the third or fourth decade (mean for
males, 120 mg; for females, 142 mg). The actual parenchymal cell mass represents about 74% of the weight
of adult parathyroid glands.
Histology (Table 1)
The capsule of the parathyroid glands consists of delicate fibrous tissue. The parenchymal cells of
adult parathyroid glands are arranged in solid groups, cords, nests, and follicle-like structures, with
intervening stromal tissue. The follicle-like structures often contain eosinophilic PAS-positive
material resembling colloid. This material is not immunoreactive for thyroglobulin. A resemblance of
this colloid-like substance to amyloid at a light microscopic and ultrastructural level has been noted.
The adult parathyroid contains predominantly chief cells, though they are larger and contain more
intracytoplasmic fat than the chief cells in children. The cytoplasm is amphophilic or slightly
eosinophilic to somewhat clear. Prominent lipid droplets are present in 70-80% of the chief cells.
Chief cells which are "active" in the secretory process contain little or no cytoplasmic lipid. They
also contain more secretory granules as evidenced by silver stains or by chromogranin staining. The
nuclei of chief cells are round and tend to be rather hyperchromatic due to a coarse chromatin pattern
typical of neuroendocrine cells. Oxyphilic cells and transitional oxyphilic cells are also found in the
adult parathyroid. Transitional oxyphilic cells appear to represent an intermediate phase in the
transition from chief cells to oxyphilic cells. The oxyphilic cells may be interspersed in small groups
among the chief cells, or they may form nodules. The relative number of oxyphilic cells and the tendency
to form oxyphilic cell nodules increases with age. The oxyphilic cells are larger than chief cells and
have striking eosinophilic granular cytoplasm. Ultrastructural studies indicate that the cytoplasmic
granularity results from the enormous number of mitochondria in these cells. Although the oxyphilic
cells in normal glands do not seem to be actively secreting parathormone, hyperfunctioning oxyphilic
neoplasms have been reported. The nuclei of oxyphilic cells are usually pyknotic.
In infants and children the chief cells are arranged in solid sheets, with minimal intervening
stroma. Oxyphilic and transitional oxyphilic cells are not normally observed. The chief cells are
small, and have faintly eosinophilic cytoplasm with less intracellular fat than the cells of adult
parathyroid glands. More variable architectural features appear beginning in puberty with the
accumulation of more stromal tissue. Within the glands there is an arborizing meshwork of arterioles, venules, and a
myriad of capillaries, which gives the glands an extremely rich blood supply. The glands of children are
very cellular with little stromal collagen and very few stromal fat cells. The number of stromal fat
cells begins to increase around puberty and continues to increase until the third to fifth decades.
Stromal fat is quite variable in its distribution among individuals as well as within a single gland,
making the relative percentage of stromal fat a tenuous feature in evaluation of parathyroid
proliferative diseases. Women generally have a higher percentage of stromal fat than men. In generally
stromal fat represents about 50% of total stromal volume. Stromal fat content is affected by several
variables, including nutrition, body habitus, general state of health, and heredity.
Hyperparathyroidism is a metabolic derangement characterized by the increased production of
parathyroid hormone. Serum calcium may be low, normal or elevated. Hyperparathyroidism includes
primary, secondary and tertiary
In primary hyperparathyroidism excess parathyroid hormone originates from one of the parathyroid
proliferative diseases, including adenoma, hyperplasia or carcinoma. In this setting the serum calcium
levels are typically increased. Solitary adenomas account for >80% of cases of hyperparathyroidism.
See below for a more detailed discussion on parathyroid hyperplasia, adenoma and carcinoma.
Secondary hyperparathyroidism is an increase in parathyroid parenchymal cell mass of multiple glands
in response to a known clinical stimulus for increased secretion of parathyroid hormone. These
conditions are usually characterized by hypocalcemia and hyperphosphatemia.
Causes of secondary hyperparathyroidism include chronic renal failure (most common), dietary vitamin
D deficiency or abnormalities of vitamin D metabolism, malabsorption, and pseudohypoparathyroidism.
Secondary hyperparathyroidism occurs over broad age range, reflecting the incidence of chronic renal
failure, the most common cause of secondary hyperparathyroidism. Symptoms of secondary
hyperparathyroidism are primarily related to parathyroid hormone-mediated bone resorption which results
in osteomalacia and osteitis fibrosa cystica. Abnormal calcium deposits in the soft tissues,
particularly in a periarticular distribution, may be seen. Laboratory studies reveal elevation of
parathyroid hormone levels with hypocalcemia and hyperphosphatemia.
Tertiary hyperparathyroidism an absolute increase in parathyroid parenchymal cell mass associated with
autonomous hyperfunction and resultant hypercalcemia in a patient with previously known secondary
hyperparathyroidism following implementation of dialysis or renal
Other Causes of Hypercalcemia
Humoral hypercalcemia of malignancy (HHM) is an important clinical differential diagnostic
consideration in patients suspected of having primary hyperparathyroidism. HHM is independent of the
extent of metastatic disease involving bone, and is characterized by hypercalcemia, hypophosphatemia, and
elevated urinary cyclic AMP levels. Unlike hyperparathyroidism, serum parathormone and
1,25-dihydroxyvitamin D are suppressed. The mechanism for hypercalcemia appears to be increased bone
resorption due to a humoral factor known as parathyroid hormone-related protein. This form of
hypercalcemia was most frequent in patients with squamous cells carcinoma (lung, upper aerodigestive
tract, and female genital tract), renal cell carcinoma, and transitional cell carcinoma.
A second mechanism of hypercalcemia associated with malignancy is related directly to the osteolytic
effect of bone metastases. This form of hypercalcemia is more common in patients with breast carcinoma
and hematologic malignancies. These patients have suppressed levels of parathormone, but urinary cyclic
AMP is not elevated and parathyroid hormone-related protein has not been implicated.
Lithium therapy for psychiatric disorders has been associated with a form of hyperparathyroidism
similar to primary hyperparathyroidism, with hypercalcemia and elevated serum parathormone levels. Both
chief cell hyperplasia and "adenomas" have been described in these patients. The hyperparathyroidism
resolves after discontinuing lithium therapy; however, patients requiring lithium may be treated
successfully with subtotal parathyroidectomy.
In addition to HHM and lithium therapy other causes of hypercalcemia include familial benign
hypercalciuric hypercalcemia, vitamin D intoxication, sarcoidosis and other granulomatous disorders,
idiopathic hypercalcemia of infancy (abnormal vitamin D sensitivity), and disorders associated with high
bone turnover and hypercalcemia, including hyperthyroidism, immobilization, thiazide diuretics, and
vitamin A intoxication.
Indications for Intraoperative Consultation for Hyperparathyroidism
The major indications for intraoperative consultation of patients with hyperparathyroidism is to
determine the underlying pathologic process, which directly impacts on treatment:
- a diagnosis of parathyroid adenoma results in
excision of the involved gland alone and this treatment is curative;
- a diagnosis of parathyroid hyperplasia
results in subtotal parathyroidectomy (three and a half glands) leaving behind a small amount of
parathyroid tissue (approximately 50 gms).
- A diagnosis of parathyroid carcinoma usually
necessitates en bloc resection to include the involved gland, adjacent thyroid lobe with or without
selective neck dissection. This approach offers the best opportunity for a cure.
Surgeons Objective and Expectations of the Intraoperative Assessment of Parathyroid Exploration
The surgeon's objective in the face of a patient with hyperparathyroidism is to locate and reomove any
enlarged parathyroid glands. The surgeon expect the pathologist to:
1) identify the tissue as being of parathyroid gland origin;
2) attempt to differentiate a parathyroid adenoma from hyperplasia;
3) diagnose carcinoma;
4) do this all in a short a time period.
Practical Reality of the Intraoperative Assessment of Parathyroid Exploration
The first rule in the intraoperative consultation of parathyroid diseases is "do
not believe the surgeon that the resected tissue is of parathyroid gland origin ." The second
rule, which is mutually inclusive of the first rule is to recognize the resected tissue as parathyroid
parenchyma. Once recognized as parathyroid tissue the determination of whether the resected tissue is
normal, abnormal or indeterminate can be undertaken (Table 1).
Handling of Resected Parathyroid Glands
1) Record location of excised tissue;
2) Record the size and weight of the excised glands after removing the
surrounding fat (inform surgeon of these findings). Glands weighing greater than 100 mg are considered
pathologic, whereas a normal gland typically weighs 35 mg. Do not remove "fat" that is closely apposed
to any nodules as this tissue may be representative of a cap of normal parathyroid tissue a potential key
histologic feature in the diagnosis of parathyroid adenoma.
3) Gross examination with attention to the external appearance, color
and consistency of the excised gland;
4) Perform frozen section.
Is the inking of parathyroid glands necessary? Typically excised parathyroid gland do not require
surgical ink but if the excised gland is adherent to surrounding structures suggesting the possible
diagnosis of carcinoma then evaluation of surgical margins becomes important and requires the inking of
Microscopic Findings at Frozen Section
In the presence of an enlarged (size and weight) parathyroid gland the histologic findings are almost
invariably abnormal. These changes may include increased cellularity and decreased stromal fat. A
capsule may or may not be present and a rim of residual normal or atrophic parathyroid tissue may or may
not be present. In this setting if the surgeon indicates that the remaining parathyroid glands are
normal and/or samples of additional parathyroid glands show no abnormalities then a diagnosis of "enlarged parathyroid gland consistent with adenoma" can be made. If more than one
parathyroid gland is enlarged, including microscopic evidence of increased cellularity with decreased fat
the patient may have parathyroid hyperplasia. Clinical information of whether the patient has a primary
diagnosis of PPD, secondary hyperparathyroidism or familial disease is helpful in the diagnosis. Such
examples can be signed out as "cellular parathyroid tissue" or "parathyroid proliferative disease" with the definitive diagnosis pending permanent
sections with appropriate clinical correlation.
Microhyperplasia (see Cusumano et al) in grossly normal (size and weight)
glands classified into two groups:
The differentiation of an adenoma from hyperplasia in a single enlarged gland
cannot be made by histopathologic evaluation; detailed clinical information (pre- and postoperative) is
required to render this diagnosis . In the face of abnormal parathyroid tissue in a single gland
reported as "abnormal parathyroid gland (parathyroid proliferative disease) consistent with adenoma or
hyperplasia", the pathologist should ask the surgeon about the status of the other parathyroid glands and
should also request a biopsy (i.e., incisional biopsy) from one or more of the other parathyroid glands.
In the presence of a borderline enlarged parathyroid gland with the other glands reported as normal, the
- Class I – normal in size and histologically
- Class II – normal in size but histologically
hypercellular with decreased fat (not thought to produce hypercalcemia);
- Class III – normal in size but with nodular
pattern, hypercellularity or oxyphilic nodules (considered clinically significant);
- Class IV – enlarged glands (100 miligrams or
more) with microscopic abnormalities (clinically significant).
- an adenoma is present that has not been identified and continued surgical exploration is indicated;
- the borderline enlarged gland is responsible
for the hyperparathyroidism but this requires clinical correlation;
- the elevated biochemical findings may be due
to non-parathyroid hypercalcemic diseases.
Flow Chart for Intraoperative Assessment for Hyperparathyroidism :
1. Parathyroid confirmed → determine hypercellularity
→ enlarged, hypercellular gland confirmed → report as parathyroid proliferative disease c/w
adenoma or hyperplasia → examine at least one additional parathyroid gland → normal or
atrophic → c/w parathyroid adenoma
→ abnormal (hypercellular) → c/w
2. Parathyroid not confirmed → repeat biopsy
Pitfalls And/or Issues in the Intraoperative Evaluation of Parathyroid Glands
Parathyroid tissue may be difficult to distinguish grossly from other tissues in the neck, including
thyroid, lymph nodes, fat, and ectopic thymus. Frozen section may be requested on these tissues.
1) The differentiation of parathyroid tissue from
thyroid tissue may be problematic and is the most common reason for a deferred or incorrect frozen
section diagnosis. Histologic patterns that may result in misinterpretation include:
2) Lymph nodes can be mistaken for parathyroid tissue as a result
freezing artifact with the presence of tissue clefts and formation of ice crystals giving the impression
of stromal fat.
- follicle formation; in the presence of a
microfollicular pattern features that may point to parathyroid gland rather than thyroid tissue include
the presence of solid, sheet-like growth in the nodule, a variety of cell types (e.g., chief cells, clear
cells, oxyphil cells), the absence of a lymphocytic cell infiltrate, fat cells within the nodule, a "cap"
of normal, fat-containing parathyroid tissue adjacent to the nodule;
- clusters of oxyphilic cells;
- stromal changes of thyroid gland simulating
that of parathyroid gland.
3) The presence of a rim of adjacent parathyroid
tissue is helpful in the diagnosis of parathyroid adenoma; however, this finding is not
unequivocally diagnostic of a parathyroid adenoma. A rim of adjacent parathyroid tissue is seen in 30 to
50% of cases at the time of frozen section and the pathologist cannot rely on this criterion alone to
diagnose parathyroid adenoma. Further, a rim of normal parathyroid tissue may be seen in association
with parathyroid hyperplasia. The most reliable distinction between parathyroid adenoma and parathyroid
hyperplasia is made by thorough histologic evaluation of one or more additional parathyroid glands. It
should be noted that parathyroid hyperplasia may be dyssynchronous so that a hyperplastic gland may be
only minimally enlarged.
4) The greatest source of error in the intraoperative diagnosis of PPD
is the overdiagnosis of parathyroid hyperplasia. However, this issue is currently less likely to be
problematic as pathologists have become more aware of this diagnostic pitfall and there is a tendency for
surgeons to favor resection of only grossly enlarged glands. As such, the false-positive diagnosis of
hyperplasia is close to zero. Pathologists can minimize the overall error rate by being aware of the
diagnostic pitfalls surrounding the intraoperative evaluation of parathyroid glands and by working in
close communication with our surgical colleagues.
5) The presence of stromal fat cannot be
used to exclude the diagnosis of adenoma as adenomas may contain variable amount (some to abundant) of
6) The issue of multiple adenomas is
controversial. Multiple adenomas have been reported with as high an incidence of 9.4% (see Tezelman et
al). This is in contrast reports in which multiple adenomas were not present in a large cohort of cases
of consecutive explorations for primary hyperparathyroidism (see Wang). Surgeons who accept the
existence of double adenomas advocate for routine bilateral neck exploration as the enlarged glands are
approximately equally distributed on both sides of the neck (see Tezelman et al).
7) False positive and false negative diagnoses can occur in the
interpretation of parathyroid carcinoma.
Intraoperative Cytologic Preparations in the Identification of Parathyroid Tissue
Several studies have documented the increased diagnostic accuracy of intraoperative cytology (touch
imprint preparation) in the confirmation/identification of parathyroid tissue (Geelhoed and Silverberg;
Shidham et al). However, the reliability of touch imprint preparation remains controversial thereby
hindering its acceptance as a replacement for frozen section examination (Yao et al).
Reexploration for Persistent or Recurrent Hyperparathyroidism
Persistent disease is defined as hyperparathyroidism that occurs within 6 months of prior surgery and
recurrent disease is defined as hyperparathyroidism that occurs greater than 6 months after prior
surgery. Due to alterations of the surgical anatomy, the identification of parathyroid glands during
reexploration may prove difficult and the abnormal gland may be ectopically situated. The scarring in
the area may result in adhesions creating surgically difficulty in removal of the parathyroid glands.
This clinical information may suggest a parathyroid carcinoma (see next section).
Parathyroid carcinoma typically presents as mass that is adherent to adjacent structures. The latter
would be indicative of invasion and invasion would be diagnostic for carcinoma. In cases suspected
parathyroid carcinoma sampling the peripheral aspects of the lesion may provide the greatest yield in
identifying invasion. In the face of a parathyroid carcinoma the mass is excised en bloc and the
evaluation of surgical margins is critical to determining that the tumor has been completely excised.
However, in the absence of invasion the light microscopic features may be suggestive of parathyroid
carcinoma but the frozen section diagnosis of parathyroid carcinoma can be extremely challenging.
Pitfalls in the diagnosis of parathyroid carcinoma may include:
- prior violation of the neck either by
previous surgery, fine needle aspiration biopsy of spontaneous infarction may result in adherence of the
gland to adjacent structures, fibrous bands coursing within the gland and/or necrosis. In contrast to
carcinoma the adhesions in benign disease are usually easily dissected, there is evidence of hemorrhage
(and other degenerative changes) within the fibrous bands and the necrosis due to trauma or spontaneous
infarction is usually large and confluent;
- Mitotic figures can be seen in benign
parathyroid lesions; the presence of mitoses is not in and of itself indicative of carcinoma
PPD in "Ectopic" Sites
PPD may occur within the thyroid gland or thymus. These lesions are uncommon and typically are benign
(i.e., adenoma). Differentiating parathyroid from thyroid may be problematic (see above) and may require
immunohistochemical stains (e.g., chromogranin, PTH, thyroglobulin). Rare examples of intrathyroid
parathyroid carcinoma have been reported (see Crescenzo et al).
Adjunct Methods in the Intraoperative Evaluation of PPD
The use of intraoperative fat stains for the evaluation of parathyroid tissue is based on the fact
that parenchymal cells in normal glands contain abundant cytoplasmic lipid droplets while the
intracellular or parenchymal lipid content is decreased or absent in hyperfunctioning chief cells. Fat
stains may include Sudan IV, oil red O and osmium carmine. Intraoperative fat stains are technically
difficult and, therefore, are not widely utilized. Cytoplasmic lipid droplets can be evaluated in
air-dried cytologic preparations with Wright-Giemsa stain. In this setting lipid droplets are visible as
Mannitol density test or measurement provides an objective evaluation of the ratio of parenchymal to
fat cells and is based on the differences in density between parenchymal cells and stromal fat cells.
The density of the parathyroid is an indirect estimate of the lipid content of the parenchymal cell
content. With knowledge of the glandular weight and estimate of parenchymal content it is possible to
calculate the parenchymal weight. This is a test is not widely used.
Intraoperative Determination of Parathyroid Hormone Levels
Rapid intraoperative parathormone (PTH) evaluation levels by highly sensitive immunoradiometric assay
(IRMA) are used for immediate biochemical confirmation of the result of parathyroid surgery. The
parathyroid lesion is localized preoperatively and removed through a small incision. Because of the
short half-life of PTH, a serum PTH level can be drawn 15 minutes after excision of the presumed diseased
gland. The absence of a second or multiple lesions is confirmed by immediately checking blood
parathyroid hormone level via the analyzer rather than by the standard method of exploration and biopsy
of all the remaining parathyroid glands. If a significant drop is detected, cure is reasonably assured.
This allows for less invasive surgery and decreased operating time.
Accuracy of Intraoperative Confirmation of Parathyroid Tissue and Intraoperative Diagnosis
Frozen section is a highly reliable means of identifying tissue type during parathyroid exploration.
In the study by Westra et al, the frozen section accuracy rate of
distinguishing parathyroid tissue from nonparathyroid tissue was 99.2% after deferred cases were
excluded. They reported a deferral rate of 0.4% due to difficulties in distinguishing between
parathyroid gland and thyroid gland or lymph node. Factors that may contribute to difficulties in the
intraoperative diagnosis of parathyroid gland abnormalities include (separately or in combination):
frozen section artifact, sampling error and judgmental errors. Difficulties in differentiating between
parathyroid tissue and thyroid tissue represent a major reason for deferral of cases or incorrect
Table 1. Comparison of normal parathyroid tissue to abnormal parathyroid tissue
(adapted from Chan JKC).
|Parameter ||Normal Range ||Abnormal changes|
|Number ||Usually 4, sometimes 5 |
|Size ||Length 3-6 mm|
Width 2-4 mm
Thickness 0.5-2.0 mm
|Enlarged gland greater than 6mm|
|Weight ||Approx. 30 mg each: |
- men: 120 ± 3.5 mg
- women 142 ± 5.2 mg
|Any gland weighing greater than 60 mg|
|Percentage Fat ||Approx. 17% rarely more than 50%; more in women than in men ||Complete absence or very few intraparenchymal fat cells|
|Intracytoplasmic lipid ||Abundant ||Absent or scanty|
Parathyroid Proliferative Diseases (PPD)
PPD include adenoma, hyperplasia and carcinoma (Table 2). The
classification of nonneoplastic lesions and neoplasms of the parathyroid gland are listed in Tables 3 and 4, respectively. Clinical and pathologic
findings seen in parathyroid carcinoma are detailed in Tables 5 and 6, respectively.
Table 2. Parathyroid Proliferative Diseases: Comparative
g = grams; N-to-C = nuclear-to-cytoplasmic; * = particularly in cases of familial hyperparathyroidism;
MEN = Multiple Endocrine Neoplasia syndrome.
| ||Hyperplasia||Adenoma ||Carcinoma|
|Gender; Age ||Slight female predilection; most common in 5th-6th decades ||More common in women; most common in 4th decade ||Equal gender predilection; wide age range|
|Clinical ||Asymptomatic or complaints of lethargy, weakness, polyuria, polydipsia, arthralgia, constipation, and depression ||Similar to hyperplasia ||Similar to hyperparathyroidism of benign etiology but more severe due to the higher serum calcium levels; higher proportion of renal disease (nephrolithiasis) and bone disease; peptic ulcer disease; palpable neck mass more common than in adenoma|
|Serum CA++ ||11.7 mg/ 10 ml (average) ||12.5 - 13.5 mg/10 ml ||Often > 14 mg/ 10 ml|
|Intra-operative findings||2 or more glands enlarged, easily dissected. Enlargement may be very asymmetrical||1 gland enlarged; easily dissected; more frequent in lower glands or ectopic sites||1 gland enlarged; often adherent to surrounding tissues|
|Weight ||Total gland weight usually < 1g, but may be up to 5 g ||0.3- 1.0 g commonly, but may weigh several grams in patients with bone disease ||> 1.5 g (often much larger)|
|Capsule ||Circumscribed by capsule of parathyroid gland, may be incomplete. No compressed rim of atrophic or normal parathyroid tissue ||Thin tumor capsule, often surrounded by rim of uninvolved parathyroid which may appear atrophic ||Thickened capsule; rim of normal parathyroid rarely seen|
|Gross Appearance ||Gray-brown, soft. Cut surface may be homogeneous or nodular. Lacks fibrous bands ||Red-brown, firm. Usually homogeneous, lacks fibrous bands ||Gray-white, firm, often lobulated or irregular. Fibrous bands often produce coarse nodularity|
|Histologic growth pattern ||Diffuse or nodular, sometimes pseudofollicular or acinar ||Diffuse or nodular, frequently pseudofollicular or acinar ||Diffuse, nodular, pseudofollicular, or acinar; often trabecular|
|Cytologic features||Chief cells predominate; transitional and oxyphilic cells often present||Chief cells predominate, but mixture of chief, transitional and oxyphilic cells may be seen; rarely, purely oxyphilic||Cells usually resemble chief cells, but variable cytoplasmic oxyphilia may be seen; cells borders often indistinct|
|Intracyto-plasmic lipid||Decreased||Decreased in tumor; abundant in atrophic rim of parathyroid||Usually absent|
|Stromal fat cells||Scanty to absent||Usually absent in tumor; present rim of atrophic parathyroid||Absent|
|Nuclear morphology||Normal to slightly increased N-to-C ratio; usually without nuclear pleomorphism||Nuclei enlarged, with variability in size; scattered groups of large pleomorphic, hyperchromatic nuclei, or multinucleated cells||Increased N-to-C ratio; enlarged atypical nuclei, often with a very monotonous pattern; prominent nucleoli|
|Nucleoli ||Inconspicuous to small ||Inconspicuous to small ||Frequently prominent and enlarged|
|Mitoses ||Usually rare||Usually rare (occasionally > 1 per 10 high power fields)||Usually present (80% of cases), may include atypical mitoses; may be numerous|
|Capsular and vascular invasion ||Absent ||Absent; entrapment of tumor cells may occur in capsule if degenerative changes present ||Capsular invasion present in two thirds; may involve only capsule or extend into adjacent tissues; Vascular invasion present in 10-15%; usually in capsular vessels|
|Rest of gland ||Entire gland is abnormal ||Normal or atrophic ||Normal|
|Deg. Changes ||May be seen in very large glands; includes hemorrhage, areas of fibrosis, and cystic change ||Common, especially in larger adenomas; includes hemorrhage, fibrosis, hemosiderin-laden macrophages and cystic change; sometimes calcification ||Tumor cell necrosis; calcification and cystic changes may be present|
|Treatment ||Subtotal parathyroidectomy with surgical removal of 3 glands leaving a remnant of the 4th or total parathyroidectomy* with autotransplantation of parathryoid tissue in forearm||Surgical removal of the enlarged gland ||En bloc resection, including ipsilateral thyroid lobe and adjacent soft tissues and lymph nodes|
|Prognosis ||Excellent ||Excellent ||Up to 50% of patients are cured by en bloc resection; considered an indolent malignancy even in presence of recurrence or metastasis with long survival even after recognition of tumor recurrence; morbidity and mortality correlate to complications of severe hypercalcemia|
|Recurrence and Metastasis ||Recurrence in approximately 16% of cases due to inadequate neck exploration and may not be evident for years ||Absent ||Recurrence in two thirds of patients usually within 3 years of the first surgery; metastasis is 35%, is a late event usually preceded by local recurrence; most commonly to lung, cervical lymph nodes, and liver|
|Famial and/or MEN association ||Yes, in approximately 20% of cases ||Uncommon ||Rare|
Table 3: Non-Neoplastic Lesions of the Parathyroid Glands
|Primary Chief Cell Hyperplasia|
Water-Clear Cell Hyperplasia
Table 4: Neoplasms of the Parathyroid Glands
Table 5: Clinical Features Associated With Malignancy in Parathyroid Neoplasms
|Serum calcium level > 14 mg/100ml|
Serum parathormone levels 2-3 times normal
Severe metabolic manifestations: nephrolithiasis, bone disease, etc.
Palpable neck mass
Difficulty in surgical dissection
Table 6: Pathologic Features Associated with Malignancy in Parathyroid
|Large size (mean weight 6.7 g) |
Adherence thyroid tissue
Irregular contour; lack of distinct encapsulation
Fibrous bands within tumor
Mitotic activity (especially > 5 per 10 HPF)
Capsular invasion, especially with extraglandular extension
Spindling of tumor cells
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