Hyperparathyroidism

Hyperparathyroidism’ A Clinicopathologic

Evaluation

JOE R. UTLEY, M.D. ANDWILLIAM C. BLACK, M.D., St. Louis, Missouri

eight female and eleven male patients. Thirtyone were Caucasian and seven were Negro. The incidence was greatest in the sixth decade. Five cases occurred in a single family [a]. Clinical Manifestations. Table I shows the clinical manifestations in these thirty-nine patients. Renal symptoms, which included urinary calculi, nephrocalcinosis, and uremia, occurred in twenty-four patients (61 per cent). Urinary calculi occurred in twenty-one persons. In three patients without a history of calculi nephrocalcinosis and uremia developed. Osseous manifestations occurred in seventeen patients (44 per cent). These symptoms included generalized demineralization, fractures, kyphosis, bone pain, giant cell tumors, bone cysts, or loss of the lamina dura as seen on dental x-ray films. Ten patients (26 per cent) had central nervous system manifestations. Included in this group were patients with mental confusion, depression, suicide attempts, anxiety, stupor, hysteria, and personality change. There were seven patients with manifestations in the gastrointestinal tract (18 per cent). Each of these patients had peptic ulcer disease and one of them also had recurrent pancreatitis. Twenty-one patients had manifestations in only one organ system. The percentage in which each organ system was involved in this group is shown in the first column of Table I. Many patients had complaints related to more than one organ system. These involved two, three, or four organ systems and occurred in any combination. If multiple organ system manifestations occur at random, the expected percentage of each combination will be the product of the percentages that each member of the combina-

From the Department of Surgery and Surgical Pathology, IYashington University Srhool of Medicine, St. Louis, Missouri.

OPEand co-workers [1,2] and Roth [3] have emphasized the importance of the histopathology of the parathyroid glands in determining the extent of surgical exploration and resection at the operating table. It is often dificult to determine on the basis of gross and microscopic examination of one or even two glands at the time of operation whether one is dealing with single or multiple adenomas or with primary chief cell hyperplasia. Despite thorough search, the surgeon often finds fewer than four parathyroid glands. For patients in whom less than four glands are examined, proof of the identity of the disease (adenoma versus hyperplasia) can only be based on follow-up information. Current concepts indicate that removal of a solitary adenoma will be curative, whereas removal of only one or two glands involved with primary chief cell hyperplasia will likely be followed by persistent or recurrent hyperparathyroidism. We have studied the clinical features, pathology, and long-term postoperative follow up in thirty-nine patients with primary hyperparathyroidism seen at Barnes Hospital. This study indicates that the differentiation of adenoma from primary chief cell hyperplasia is not as exact as has been thought. c

CLINICALMATERIAL Thirty-nine patients with primary hyperparathyroidism were operated upon at Barnes Hospital from 1956 to 1966. There were twenty-

* Presented at the Nineteenth Annual Meeting of the Southwestern Phoenix, Arizona, April l@-13, 1967. 788

Surgical Congress,

_4merican Jouvnal of Surgery

Hyperparathyroidism TABLE CLILICAI.

>lASIFESTATIONS

1

OF HTPERPARATHYROIDISM

All Cases Manifestation

789

No.

Per Cent

~~~__ Expected Incidence* (Per Cent)

Confirmedt

adenoma SO.

Per Cent ___~~

--In one system Rena1 (38) Osseous (38) Central nervous system (147;) Gastrointestinal (10%) In two systems Renal-osseous Renal-central nervous system Renal-gastrointestinal Osseous-gastrointestinal Osseous-central nervous system Central nervous system-gastrointestinal In three systems Renal-osseous-central nervous system Osseous-central nervous system-gastrointestinal Renal-osseous-gastrointestinal Renal-central nervous system-gastrointestinal In four systems Renal-osseous-central nervous systemgastrointestinal

8 8 3 2

20 20 8 5

5 4 4 1

13 10 10 2.6

1-I

3

8

1

2.6

s

Chief Cell Hyperplasia so.

Per Cent

_~____

23 18

1

12

1

12

4 3 4

18 14 18

2 1 1

25 12 12

20 5 1 0.5

1

5

2

25

2

1

5

i;.6 3.6 5 1

* In patients with single system manifestations the percentage of involvement of each organ system was calculated (column 1). The expected incidence of multiple organ system involvement is calculated by multiplying the incidence of each single system involvement. Thus, the expected incidence of renal and osseous involvement is 0.38 X 0.38 = 0.14. t Diagnosis confirmed on basis of follow-up information and pathologic material. In seven patients insuffkient pathologic material was available or follow-up period too short to confirm the diagnosis.

tion occurred as single organ system manifestations. Thus, renal and osseous manifestations each occurred in 38 per cent of the patients with single system involvement. The expected incidence of the combination of renal and osseous manifestations is 0.38 X 0.3s = 0.14 (14 per cent). The x2 test showed that there was no statistical difference between the observed incidence of various combinations and the expected incidence. The cases of adenoma and chief cell hyperplasia listed in Table I are only those confirmed by follow-up study. There is no statistically significant difference between the incidence of various manifestations in adenoma and primary chief cell hyperplasia (x2). There is no correlation between the size (mean chordal dimension) of the involved parathyroid gland and the duration of symptoms. (Fig. 1.) The size of the gland had no correlation with the serum calcium (Fig. 2), alkaline phosphatase (Fig. 3), or the tubular reabsorption of phosphate (Fig. 4). The abnormal paraVol. 114. November

I967

thyroid gland was palpated preoperatively in seven cases. The mean chordal dimension (MCD) of the palpable glands was not significantly different from that of those glands which were not palpable. (Fig. 5.) The size of the glands which caused esophageal displacement on barium swallow was not significantly different from the size of those which did not. (Fig. 6.) No significant difference was found in the serum alkaline phosphatase level in patients with and without osseous manifestations. However, all patients with alkaline phosphatase levels above 10 Bodansky units had osseous manifestations. (Fig. 7.) There was no difference in the tubular reabsorption of phosphate in patients with and without urinary calculi. (Fig. 8.) No correlation was found between serum calcium level and osseous manifestations. (Fig. 9.) The serum calcium levels were the same in patients with and without urinary calculi. (Fig. 10.) There is no significant difference in the serum calcium level in patients with and

Utley and Black

790 35 r

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M C D (cm)

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(BodonskyUnits) FIG. 1. Size of parathyroid adenomas related to duration of symptoms. ALKALINE PHOSPHATASE

FIG. 2. Size of parathyroid adenomas related to serum calcium values. FIG. 3. Size of parathyroid adenomas related to serum alkaline phosphatase values.

without central nervous system manifestations. No patients with serum calcium levels above 15 mg. per cent had central nervous system mani-

festations. (Fig. 11.) No significant difference

in levels of serum calcium, phosphorus, or alkaline phosphatase or in the tubular reabsorption of phosphate could be shown between patients with adenoma or primary chief cell hyperplasia. (Fig. 12 through 15.)

Pathology. Single adenomas are the most frequently reported cause of hyperparathyroidism. Other types of parathyroid disease which produce hyperparathyroidism are water clear cell hyperplasia, primary chief cell hyperplasia, 4

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90

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90

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FIG. 4. Size of parathyroid adenomas related to tubular reabsorption of phosphate.

oxyphil adenoma, and parathyroid carcinoma. At Barnes Hospital one oxyphil adenoma was found incidentally at the time of thyroidectomy and was not associated with clinical hyperfunction. This series is comprised only of cases of adenoma and primary chief cell hyperplasia; there are no cases of water clear cell hyperplasia or carcinoma. Primary chief cell hyperplasia, which was described by Cope et al. [2] in 1958, involves all parathyroid glands. These diseased glands are more cellular and contain less fat than the normal glands. There are often pseudopod-like projections from their surface. Adenomas usually occur singly. Patients with two adenomas have been frequently reported. Whether three adenomas may occur synchronously in the same patient is controversial. A gland containing an adenoma usually has a rim of compressed parathyroid gland at the periphery. Adenomas contain little or no fat. This study could not establish the presence of atrophy in the other glands associated with an adenoma. The parathyroid glands normally may vary in their cellularity and the amount of fat they contain. Atrophy cannot be established by histologic section alone for only careful appraisal of the size of all parathyroid glands can establish the presence of atrophy. This inAmerican

Journal of Surgery

Hyperparathyroidism

791

90

.

. SO i 70 : h

.

60 :

i

.

0’

NOT Palpable

O\

Palpable

NO Esophageal

5

O+YK-mE OSSEOUS MANIFESTATIONS

Dksplacement

FIG. 5. Size of palpable and nonpalpable

parathyroid

FIG. 6. Presence or absence of displacement adenomas. FIG. 7. Osseous manifestations

of the esophagus on barium swallow, related to size of parathyroid

related to serum alkaline phosphatase

formation is seldom available in surgical material. Roth and Castleman indicate that there is more variability in cell types and cellular pattern in adenomas than in primary chief cell hyperplasia. Study of the material in this series shows that the histopathology may be very similar in adenomas and primary chief cell hyperplasia. The distinction may be especially diEi-

IO WITHOUT

WITH OSSEOUS

MANIFESTATIONS

9

8

adenomas.

values.

FIG. 8. The presence or absence of urinary calculi related to tubular reabsorption

IO

CALCULI

7

6

of phosphate.

cult to make by frozen section. Thus, the number of glands involved is of great importance in differentiating chief cell hyperplasia from adenoma at the time of operation. This differentiation is important to determine the quantity of parathyroid tissue which should be removed or examined. Removal of a solitary adenoma should be curative. In primary chief cell hyperplasia resection of all but enough tis-

WITHOUT

WITH CALCULI

10

FIG. 9. The presence or absence of osseous manifestations

MANIFESTATIONS

CNS

11 related to serum calcium values.

FIG. 10. The presence or absence of urinary calculi as related to serum calcium values. FIG. 11. The presence or absence of central nervous system manifestations serum calcium values. Vol.

114.

n’owmber

1967

as related to

Utley and Black

792

. .

. ..

.. ........... . .

ADENOMA

CHIEF CELL HYPERPLASIA 12

FIG. 12.

Serum

CHIEF CELL HYPERPLASIA

ADENOMA

13

calcium values in parathyroid adenoma and chief cell hyper-

plasia. FIG. 13. Serum phosphorous values in parathyroid adenoma and chief cell hyperplasia.

sue to maintain a normal serum calcium level is necessary to prevent recurrent hyperparathyroidism. Five patients in this series have had recurrent hyperparathyroidism after exploration and resection of one or two enlarged glands. The gross and microscopic features of parathyroid tissue found at re-exploration have shown that the initial pathologic diagnosis of adenoma

$I/,.; 7 ADENOMA

14

q

A,E1,,,

CHIEF CELL HYPERPLASIA

CHIEFml

““Pm~LAsIA

15

14. Serum alkaline phosphatase values in parathyroid adenoma and chief cell hyperplasia.

FIG.

FIG. 15. The tubular reabsorption of phosphate in parathyroid adenoma and chief cell hyperplasia.

was in error and that the basic process was one of chief cell hyperplasia. illustrative case reports.

The following are two

CASE I. The patient (H. M.) was a fifty-three year old Caucasian man seen in 1958 with a thirty year history of urinary calculi; he also had a history of duodenal ulcer. Nephrocalcinosis was found on intravenous pyelograms. Results of laboratory tests were as follows: serum calcium 12.5 mg. per cent, alkaline phosphatase 9.1 Bodansky units, tubular reabsorption of phosphate 65 per cent, blood urea nitrogen 16 mg. per cent. The right superior (MCD 2.3 cm.) and the left superior (MCD 2.0 cm.) parathyroid glands were removed and diagnosed as adenomas. No other parathyroid tissue was identified. The patient became normocalcemic postoperatively, but within two years had recurrent hypercalcemia. He was operated upon again and an enlarged parathyroid gland was found between the esophagus and trachea on the right side (MCD 1.2 cm.). Follow-up study for one year shows the patient to be normocalcemic. The pathologic findings in this case are consistent with primary chief cell hyperplasia.

Comment: This patient was thought to have two adenomas on the basis of pathologic examination but follow-up study and further exploration showed the lesion to be primary chief cell hyperplasia. CASE II. The patient (B. M.) was a forty year old Caucasian woman seen in 1959 with urinary

AmericanJournal

oj Surgery

793

Hyperparathyroidism TABLE DIAGNOSES

AT TIME

II

OF OPERATION

FOLLOW-UP

so.

Diagnosis

I

123,567

I

a

YEARS FOLLOWUP FIG. 16. Follow-up period in this series. Seventy-two per cent of the patients were followed up for three years and 44 per cent were followed up for five years or longer.

calculi, depression, and suicide attempts. Results of laboratory tests were as follows: serum calcium 13.4 mg. per cent, serum phosphorus 1.8 mg. per cent, alkaline phosphatase 3.5 Bodansky units, tubular reabsorption of phosphate 78 per cent, blood urea nitrogen 12 mg. per cent. There was no evidence of decreased renal function. The left upper gland was removed and contained a rim of compressed residual parathyroid tissue at the periphery; this gland was interpreted as a parathyroid adenoma. No other parathyroid tissue was identified. The patient’s serum calcium level returned to normal, but hypercalcemia recurred two years later. The right superior (MCD 0.i cm.) and right inferior (MCD 0.4 cm.) parathyroid glands were then resected. The patient became normocalcemic and remained so for two years.

Comment: This is a case of primary chief cell hyperplasia in which one gland had the pathologic characteristics of an adenoma. The pathology of the first gland removed was typical of adenoma. The final diagnosis in this patient was primary chief cell hyperplasia, a distinction which was clear only after follow-up study. RESULTS

In establishing a final pathologic diagnosis in these cases we have utilized the status of the patient postoperatively with the longest follow-up period possible. Follow-up data were obtained in thirty-three of thirty-nine cases. Seventy-two per cent were followed up for three years or more and 44 per cent were followed up for more than five years. (Fig. 16.) A definite pathologic diagnosis could be made in thirty-two cases. Seven cases were indetenninate because they could not be classified detiVol. 114, November

1967

Adenomas one Two Three Chief cell hyperplasia Chief cell hyperplasia and adenoma Two normal glands Indeterminate

AND AFTER

STUDY

of

Diagnoses at First Operation

2i 4 2 1

.

1 1

h-0. of

Diagnoses after Follow-Up Study

22 Ib

7

nitely as adenoma or primary chief cell hyperplasia due to indeterminate pathologic findings and/or inadequate postoperative follow up. The final diagnosis has been based on the status of four glands or on the basis of follow-up data when less than four glands have been found. Table II shows the diagnosis made at the time of the original operation and diagnoses made after the patients have been followed up. Twenty-two patients having lesions originally denoted as solitary adenomas and who had adequate follow-up study had no recurrent hyperparathyroidism and the diagnosis of solitary adenoma was substantiated. One patient originally diagnosed as having a solitary adenoma has recurrent hypercalcemia and urinary calculi but has not yet been reoperated upon. In another patient in whom the diagnosis of solitary adenoma was made recurrent hypercalcemia developed and two hyperplastic glands were found on re-exploration. Three of the four patients diagnosed as having double adenomas were not followed up. The fourth patient required re-exploration and was proved to have primary chief cell hyperplasia (case I). Two patients were originally diagnosed as having three adenomas each. They are now classified as having primary chief cell hyperplasia. One patient previously thought to have an adenoma with chief cell hyperplasia in two other glands now appears to have primary chief cell hyperplasia. A patient in whom two glands were thought to be normal was re-explored and the diagnosis of primary chief cell hyperplasia was established. The cases previously diagnosed as multiple

Utley and Black

794

TABLE III NUMBER OF GLANDS FOUND AT ORIGINAL OPERATION AND RECURRENCE OF HYPERPAEATHYROIDISM IN PATIENTS

FOLLOWED

TABLE FIRST

OPERATION

UP

Patients with No Recurrence

Found

1

7

6

3

8

4

7

adenomas

sis of

in fact,

be

primary

chief

double

follow-up

adenoma

study,

and

who

recurrent

ism subsequently

;

2

3

cell

had

adequate

hyperparathyroid-

developed.

If a gland consistent with an adenoma is found at operation, the tedious search for the other glands is often not pursued to completion. Table III shows the fate of the patients who have the

been

adequately

number

original whom

of

one gland

followed

glands

operation.

thyroidism

In

two

was found

developed

up in relation

demonstrated of

nine

recurrent

as it did

at

Study

patients

0.7 0.3

Died of giant cell myocarditis one year

in

1.2 0.6

Recurrent years

hypercalcemia

in two

2.3 2.0

Recurrent years

hypercalcemia

in two

0.4 1.0

Persistent hypercalcemia years

for five

4.0 1.0 1.6

No recurrence

0.6 0.9 0.4

No recurrence

0:s 0.7 2.6

No recurrence

0.3 0.5 0.8 0.9

No recurrence

to COMMENTS

in

hyperpara-

in two

3%

in three

hypercalcemia

years

their

of eight

in whom two glands were found. In a patient in whom three glands were found, but only two were resected, recurrent hyperparathyroidism developed. No person in whom four glands were demonstrated had further hyperparathyroidism. Table IV shows the result of follow-up study in patients with a confirmed diagnosis of primary chief cell hyperplasia in relation to the number of glands resected. In both patients in whom one gland was removed recurrent hypercalcemia developed. Three of four persons in whom two glands were removed had recurrent or persistent hyperparathyroidism. No patients with three or four glands removed had further hyperparathyroidism. This indicates that in chief cell hyperplasia at least three glands must be removed to prevent recurrence. Recurrent hyperparathyroidism, when it occurred, developed within four years. patients

Recurrent

;:b

In the only patient with a diagno-

hyperplasia.

HYPERPLASIA

Results of Follow-Up

1

moved) 2 (Recurrent hypercalcemia) 1 (Recurrence of hypercalcemia ; hyperplastic gland removed) 2 (Persistent hypercalcemia; multiple urinary stones) i 1 (Recurrent hypercalcemia; patient required re-exploration)

may,

CELL

No. of Patients with Recurrence

1 (Recurrence of hypercalcemia two hyperplastic glands re-

2

Chordal Diameter (cm.)

Glands Removed

x0. of

Iv

CHIEF

Mean

No. of No. of Glands

FOR

Since

primary

scribed classified

the

tissue

composed

either

adenoma

plasia. mal

chief

The

or

and

perplasia gland.

reliable

of

adenoma

chief

gland,

how

be

made

adenoma moved?

This

patient.

If

may

norof

an

Study

of

shown

no

which chief

be made

the

cell

were

hy-

in a single

of apparent seen

residin three

cell hyperplasia. is inexact

may

the

when

depends

has

upon

the diagnosis

cell hyperplasia

single

signs.

primary

remnants

that

as

hyper-

periphery

cases

parenchyma

of primary

cells

cell

to be one of the most

criteria

Compressed

ual parathyroid

the

histologic

diagnosis

Recognizing

parathyroid chief

in these

objective and

at

thought

the histopathology reliable

dehave

of a rim of compressed

tissue

objective

was

surgeons of chief

primary

presence

parathyroid

differential

and

predominantly

has been

chief

hyperplasia

hyperfunctioning

adenoma

cases

cell

in 1958, pathologists

final

only

on what

hyperparathyroidism

of adenoma from

study

diagnosis

one

gland

happens fails

American Journal

or of a of

is reto the

to recur,

of Surgery

Hyperparathyroidism then the diagnosis of adenoma is established. Five patients in whom one or two enlarged glands have been removed have had recurrent or persistent hyperparathyroidism. Recurrent hyperparathyroidism developed as late as four years postoperatively. Presumably the interval might be longer. In the patients who have been re-explored and in whom three or more parathyroids have been removed, there has been no recurrence of hyperparathyroidism. These are cases of primary chief cell hyperplasia. The final diagnosis of multiple adenomas has not been confirmed in this series. Patients in whom the diagnosis of multiple adenomas has been made should be closely followed up for recurrent hyperparathyroidism may develop. Histologic criteria are not reliable enough to make the distinction between three adenomas and primary chief cell hyperplasia. The approach to the problem of differential diagnosis between adenoma and primary chief cell hyperplasia in this study has been that the original lesion is responsible for any recurrent hyperparathyroidism. There is no absolute proof of this since primary chief cell hyperplasia might develop after an adenoma has been removed. To establish this would require careful measurement and biopsy of all parathyroid glands associated with an adenoma and follow up of the patient. The material does not contain these data. Adenoma and primary chief cell hyperplasia may be different morphologic responses to the same stimulus. In these series are five members of the same family with hyperparathyroidism. Three had an adenoma and two had primary chief cell hyperplasia. There is no objective distinction between the compressed rim of tissue about an adenoma and the streaming of hyperplastic tissue about the gland described in some members of this family 141. The familial occurrence of hyperparathyroidism as adenoma or primary chief cell hyperplasia indicates that the genetic “stimulus” may produce either lesion. There have been several reported cases of secondary chief cell hyperplasia associated with renal failure or sprue in which an adenoma developed and produced hypercalcemia (tertiary hyperparathyroidism) [4,53. The stimulus for the secondary chief cell hyperplasia is thought to be hypocalcemia. These adenomas develop in

Vol. 114. November

1967

a “stimulated” parathyroid gland. No “stimulus” is demonstrable in primary chief cell hyperplasia. Recurrent hyperparathyroidism after the removal of one hyperactive gland may possibly be a response to an unknown stimulus. Adenomas and primary chief cell hyperplasia are probably products of the same basic process affecting the parathyroid glands. The reasons for this are as follows: (1) A single gland in chief cell hyperplasia may in every way resemble an adenoma. (2) Removal of one or two glands that appear to be adenomas may be followed by recurrent hyperparathyroidism due to primary chief cell hyperplasia. (3) Adenomas and primary chief cell hyperplasia occur in different members of the same family with hyperparathyroidism [F]. Autonomous hyperparathyroidism (tertiary hyperparathyroidism) in cases of secondary chief cell hyperplasia may be produced by an adenoma [G,S]. This also suggests a relationship between hyperplasia and adenomas. SUMMARY

Thirty-nine cases of hyperparathyroidism have been studied. Follow-up study showed that in five patients recurrent hyperparathyroidism developed. No reliable pathologic criteria were found to differentiate adenoma from chief cell hyperplasia in a single gland. Patients with primary chief cell hyperplasia may have glands that fulfill the classic criteria of adenoma. Adenoma and primary chief cell hyperplasia of the parathyroid glands may be manifestations of the same basic process. REFERENCES

1. COPE, 0. Hyperparathyroidism: diagnosis and management. Am. J. Surg., 99: 394, 1960. 2. COPE, O., DEYNES, W. M., ROTH, S. I., and CASTLEMAN, B. Primary chief cell hyperplasia of the parathyroid glands: a new entity in the surgery of hyperparathyroidism. Ann. Surg., 148: 375, 1958. 3. ROTH, S. I. Pathology of the parathyroids in hyperparathyroidism. Arch. Path., i3: -495, 1962. 4. CUTLER, R. E., REISS, E., and ACKERMAN, L. V. Familial hyperparathyroidism. :%‘a! England J. Med., 270: 859, 1960. 5. GOLDEN, A., CANAR, J. J., and KERWIN, D. M. Concurrence of hyperplasia and neoplasia of the narathvroid glands. Am. J. Afed., 38: 562, 1965. 6. HA&IS, j. C.,-ROSENBAUM, D., and O&ER, L. Primary hyperparathyroidism with parathyroid hyperplasia and adenoma in a single gland. Am. /. Cl&. Path., 45: 51, 1965.