Parathyroid Adenomas and Glands in Normocalcemic Hyperparathyroidism A Light Microscopic Study L. Grimelius, MD, S. Ejerblad, MD, H. Johansson, MD, and 1. Werner, MD
Surgical exploration of the parathyroid glands was carried out in 84 patients who had recurrent kidney stones and serum calcium levels in the upper quartile and most of whom had hypercalciuria. Parathyroid adenoma(s) were found in 19 cases, hyperplasia in 39 cases, and normal parathyroid glands in 26 cases. Postoperatively, a clinical follow-up was carried out for 2 to 5 years. No relapse has occurred in the cases with adenoma(s) but did occur in 24% of the group with hyperplasia and in 48% of the group with normal glands. The histopathologic findings are described here, while the clinical results are given in another paper. The adenomas do not differ histologically from those giving rise to hypercalcemic hyperparathyroidism. The hyperplasia was of the chief cell type and was slight in most cases. The "normal" glands did not differ from other normal glands from euparathyroid subjects. There was no significant difference in weight and histopathologic appearance between the hyperplastic glands of patients who relapsed and those who did not. Nor did the normal glands of "cured" patients differ from those of patients with relapse. However, in both these groups, some histologic features seem to indicate a favorable outcome; in the group with hyperplasia, there were higher glandular and parenchymal cell weight as well as predominance of light chief cells and small fibrotic areas. In the normal group, higher number of argyrophil cells and small fibrotic areas also seem to implicate a better prognosis. (Am J Pathol 83:475-484, 1976)
IN A PREVIOUS PAPER. Johansson et al.' described the outcome after parathxroid surgery^ of 84 patients who had had recurrent kidney stones and were suspected to have normocalcemic hyperparathyroidism. On the basis of glandular weight and histopathologic findings, the patients could be separated into three groups: those with parathvroid adenoma(s), those with hyperplasia, and those with normal glands. The best clinical results were obtained in the patients with adenomas, among whom there were no recurrences in a 2- to 5-year follow-up period; the least favorable results were in the group with normal glands. In the present paper the pathology of the parath\vroid glands will be described in detail and the histopathologic findings related to the clinical course. From the Departments of Pathology. Surgery. and Intemal NIedicine. 1 ppsala U ni%ersitv Hospital. Uppsala, Svveden. Supported by Project B76-17X-04787-O1 from the Smedish MIedic-al Research Council and b\- the MIedical Research Board of the Ss-edish Life Insurance Company Accepted for publication February 5. 1976. Address reprint requests to Dr. L. Grimelius. Department of Pathology. PO Box o.53. S-751 22. Uppsala 1, Sseden. 475
476
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The biopsy material was from 84 patients, 29 women and 55 men. The age at operation varied from 20 to 75 years; 53 patients were below 50 years. All had a historv of kidney stones, and all had serum calcium level in the upper normal quartile. In 29 patients, occasional serum calcium values of 5.3 to 5.5 mEq/liter were observed. The majority of patients had hypercalciuria; about one-third showed slightlv elevated borderline values. For details see Johansson et al. All four glands were explored. Biopsies from at least two glands for preliminary histologic examination (frozen section) were taken. When the preliminary diagnosis was adenomas, the tumors were removed, always together with the largest nonadenomatous gland. When the diagnosis was hyperplasia, the three largest glands were removed. If the fourth gland was normal-sized, it was left intact; if it was enlarged, it was partly resected. When all glands looked normal-sized, the three largest were extirpated. C
Fm
All patients were followed postoperatively during 2 to 5 (mean value 3.5) vears with regard to clinical symptoms of kidney stone disease, serum calcium levels, and urinarv calcium excretion. In some patients the level of serum PTH was also determined pre- and postoperatively (see johansson et al.l). The parathyroid glands were weighed and, depending on their size, divided into suitable pieces. The tissue was fixed in neutral formalin, dehydrated, cleared, and embedded in paraffin. The nonadenomatous glands, primarily diagnosed as normal or hyperplastic, were sectioned throughout in series of five consecutive 5-p-thick sections, with intervals of 150 p between each series. The adenomas were sectioned in three to five series of five consecutive 5-pthick sections with intervals of 300 to 500 p between the series. The sections in the different series were stained with hematoxvlin and eosin, the van Gieson stain, periodic acid-Schiff stain (PAS) with and without previous diastase digestion, and with the Grimelius silver nitrate stain.2 The amount of adipose tissue and the frequency of the different parenchvmal cell types was semiquantitatively evaluated through microscopic examination of all the hematoxylin and eosin-stained sections of each gland. The results were expressed as percent fat tissue of the total gland volume and the cell types as percent of the total number of parenchymal cells. A rough estimation of the parenchyma cell weight in the nonadenomatous glands was also made using the formula advised by Gilnour and Martin:3 (l.lxy)/(110 - 0.2z + 0.002yz), where x = total weight of the gland, y and z = percent parenchymal and fat tissue, respectively. The specific gravity of the fat tissue was taken as 0.9 and for remaining tissue as 1.1. The diagnosis of hyperplasia was primarily based on a mean glandular weight greater than 50 mg but the definitive diagnosis was based on parenchvma cell weight. The upper border value was 38 (mean weight + approximately 2 SD) according to Gilmour and Martin.'
Results Ademims
A solitary adenoma was found in 17 patients; in 2 there were two adenomas. All these patients were postoperatively free from relapse of
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Table 1 -Sex Distribution
Patients with Adenomas(s) Cured Relapsed Hyperplastic glands Cu red Relapsed "Normal" glands Cu red Relapsed Total
M
F
8 0
11 0
25 6
4
8 8 55
6
4 4
29
The subgrouping is related to the pathologic diagnosis of the glands and the follow-up results.
kidnev stone symptoms (Table 1). Regarding sex and age of the patients at the operation, see Tables 1 and 2. The mean weight and range of the adenomas are given in Table 3. In eleven of the tumors a remnant of "normal" gland tissue was seen outside the connective tissue capsule. In thirteen adenomas there was a solid arrangement of the parenchymal cells together with varying amounts of acinar and pseudoacinar structures. Six adenomas consisted of two or more parenchvmal cell nodules surrounded bv connective tissue. In the remaining two tumors there were some solid parts, some nodules. In seven adenomas there was a predominance of dark chief cells, in six, a predominance of light chief cells, and in six, there was a fairly even distribution between dark and light chief cells (Table 4). In most adenomas, some oxvphil and transitional oxyphil cells were seen, and in one adenoma these cell tvpes predominated. Nuclear polvmorphism occurred in 3 cases. In all adenomas the majority of parenchymal cells contained PASpositive diastase-digestible substance (glycogen) (Table 5). The frequency of argyrophil cells varied (Table 6). In two solid adenomas, some inTable 2-Age of the Patients at Operation Patients with Mean age (yrs) Adenoma(s) Cured 51.2 Relapsed Hyperplastic glands Cured 51.3 Relapsed 43.3 "Normal" glands Cured 41.1 52.7 Relapsed For subgroups, see Table 1.
Range (yrs) 38-68
46-59 28-65 28-55
48-64
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Table 3-Mean Weights and Range of Adenomas(s) and Glands
Patients with
N
Mean weight (mg)
Range (mg)
19 0
306
100-850
29 10
74 60
57-105 55-64
14 12
32
13-56 30-50
Adenoma(s)
Cured Relapsed Hyperplastic glands Cured Relapsed "Normal" glands
Cured Relapsed For subgroups, see Table 1.
-
41
flammator- cells wvere seen; in one of them small groups of lymphocytes occurred, in the other leukocvtes and plasma cells were seen also. In a third adenoma there were some fibrotic areas. The size and the weight of the nonadenomatous glands wvere all within normal limits as defined by Gilmour and Martin 3 and Alveryd.4 The dark chief cells predominated in almost all these glands. Hprsc
Glands
In 39 cases the parathyroid glands were classified as hyperplastic. Postoperatively, 10 of 39 patients have had recurrence of the kidney stone disease. Data of these patients regarding sex, age, and glandular w-eight and fat content are given in Tables 1-4 and 7. The glandular hyperplasia was of the chief cell type in all cases. The parenchy mal cells were arranged in cords and sheets separated by fat tissue and vessels or in more solid parts (Figures 1 and 2). In some glands, acinar and pseudoacinar structures were seen. Nodular cell arrangements were seen in one or two glands in about half the number of cases notwithstanding the subsequent outcome after surgery. The dark or light chief cells predominated in all the glands. A small Table 4-Mean Weight of the Parenchyma of the Glands Patients with Hyperplastic glands Cured Relapsed "Normal" glands Cured Relapsed
For subgroups, see Table 1.
Mean weight (mg)
Range
N
29 10
52 43
47-58 40-48
14 12
25 27
10-33 19-34
(mg)
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Table 5-Semiquantitative Estimation of the Frequency of PAS-Positive Cells in Adenomas and Glands Percent PAS-positive cells of the total number of parenchymal cells
Patients with
N
< 10
11-40
41-60
61-90
> 90
Adenoma(s) Hyperplastic glands Cured Relapsed "Normal" glands Cured Relapsed
19
0
0
0
6
13
29 10
0 0
0 0
5 0
7 7
17 3
14
0 0
0 0
0 0
6 4
8 8
12
For each case, the mean value of the PAS-posifive cell type of the 3(1 ) glands was calculated.
number of oxyphil and transitional oxyphil cells were seen in most glands. A small percentage of transitional water clear cells were also seen in about one-third of the number of glands in the subgroup "cured," but only in a few - glands in the subgroup "relapsed." Regarding the prevalence of dark cells, PAS-positive, and argyrophil cells, see Tables 6, and 8. Small fibrotic areas mainly perivascularlv wvere seen in about one-third of the glands in the "cured" group but only occasionally in the relapsed group (Figure 1). 3,
Normal Glands
Normal histology was found in 26 cases. Postoperatively, 12 of 26 patients have shown relapse of urinarv tract stones. Data of these patients regarding sex, age, and glandular anatomv are given in Tables 1-4 and 7. Large glands often contained more fat than the small ones. The parenchvmal cell arrangements were similar to those in the hyperplastic glands. Nodular cell arrangements were seen in some parts in Table 6-Semiquantitative Estimation of the Frequency of Argyrophil Cells in Adenomas and Glands
Percent argyrophil cells of the total number of parenchymal cells Patientswith
N
< 10
11-40
41-60
61-90
> 90
4 2 7 Adenoma(s) 19 6 0 Hyperplastic glands 4 7 29 0 0 18 Cured 7 0 10 0 0 3 Relapsed "Normal" glands 14 2 7 5 0 0 Cured 12 0 7 5 0 0 Relapsed For each case the mean value of the argyrophil cell type of the 3(k) glands was calculated.
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Table 7-The Mean Values of the Amount of Fat Tissue of the Parathyroid Glands (percent of the glandular volume to the nearest 5%). Mean value Range N (%) (%) Patients with Hyperplastic glands Cured Relapsed "Normal" glands Cured Relapsed
29 10
30 15
15-50 10-20
14 12
30 40
5-70 30-50
For subgroups, see Table 1.
about one-third of the glands belonging to the subgroup "cured" and in about one-fourth of the glands in the other subgroup (Figures 3 and 4). The dark or light chief cells predominated. Also, a small number of oxyphil and transitional oxyphil cells were seen in most glands. Small groups of transitional water clear cells were seen in two of the three glands in a case belonging to the subgroup "cured." This cell type was not seen in the other subgroup. Regarding the frequency of dark cells, PASpositive, and argyrophil cells see Tables 5, 6, and 8. Small fibrotic areas were found in about one-third of the glands in the "cured" subgroup but only occasionally in the other. Discussion A strict differentiation between normal and slightly hyperplastic parathyroid glands is sometimes difficult or impossible. In the present studv the glands were primarily classified with regard to glandular weight. As the glandular weight in the same patient could differ from one gland to the other, the mean weights of the extirpated glands were used. The Table 8-Semiquantitative Estimation of the Frequency of Dark Chief Cells in Adenomas and Glands
Patients
N
Percent dark chief cells of the total number of parenchymal cells 41 -60 < 10 11-40 61-90 > 90
Adenoma(s) 19 2* 4 6 7 0 Hyperplastic glands Cured 7 12 29 0 10 0 Relapsed 10 0 0 4 6 0 "Normal" glands 14 1 Cured 3 4 0 6 12 4 Relapsed 0 2 6 0 For each case, the mean value of the cell type of the 3('h) glands was calculated. * In one of the two adenomas, the oxyphil and transitional oxyphil cells predominated.
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upper mean weight limit for normal glands was set to be 50 mg, as suggested by Gilmour and Martin3 and Alveryd.' Most parathyroid glands contained fat tissue in varying amounts. Therefore, the parenchvmal cell weight should provide a more accurate comparison than the glandular weight. This parenchymal cell weight is, however, time-consuming to determine, and for practical reasons the diagnosis will usuallv be based on the glandular weight. In our study the parenchymal cell weight was calculated and the upper mean weight limit for normal glands was set to be 38 mg (Gilmour and Martin3). Five cases, originally classified as hyperplasia, had to be rereferred to the normals. The mean value of the parenchymal cell weights of the glands classified as normal in our study was slightly higher than that found in normal glands by Gilmour and Martin.3 The corresponding parenchymal cell weight for the hyperplastic glands was almost double that of the normal glands in spite of the fact that the difference in total weight was less. The majority of the subjects with hyperplasia were males. The postoperative follow-up results were remarkably better in the male group (Table 1). The striking difference indicates that a slight hyperplasia has a more severe clinical significance in the male and really means hyperparathyroidism. Even if there are no significant differences in the glandular weights and histopathologic findings between the "cured" and "relapse" subgroups, the following factors seem to be favorable for the outcome of surgery on hyperplastic parathyroid glands: higher glandular and parenchymal cell weight, predominance of light chief cells, and the occurrence of transitional water clear cells and small fibrotic areas. It is fair to assume that a higher glandular and parenchymal cell weight indicate a larger and even increased production of parathyroid hormone. The significance of the predominance of light chief cells and the occurrence of transitional water clear cells is not certain, but it may also indicate an increased endocrine activity. Nor in the normal group were there any significant differences in weights or histopathologic findings between the glands from those patients who relapsed and those who did not. However, some histologic factors seem to be favorable regarding the prognosis: the higher frequency of argyrophil cells and the occurrence of small fibrotic area(s). The pathogenesis of these fibrotic areas in hyperplastic as well as in "normal" glands is unclear. It may be that these areas are the sequel of an earlier inflammation, viz., "parathyroiditis." It is feasible that such an inflammation may turn out to be one cause of kidney stone disease by means of intermittent or transitory hyperparathyroidism.
GRIMELIUS ET AL
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of Pathology
No relapse occurred in the group of patients with parathyroid adenoma(s). It seems reasonable to assume that these neoplasms caused the symptoms of hyperparathyroidism (HPT). It is not clear why the adenomas caused normocalcemic HPT and not hypercalcemic HPT. It mav depend on a small amount of hormone being released from the neoplasm, or the hormone synthesized b- the neoplasm may have an abnormal
biologic activity. In an earlier investigation, Ejerblad et al.5 made a histopathologic study of parathyroid adenomas causing hypercalcemic HPT. They' also extirpated one of the nonadenomatous parathvroid glands which were examined in the same way. The histologic findings in both the adenomas and the nonadenomatous glands in their study were similar to ours, i.e., the adenomas and nonadenomatous glands in cases with normocalcemic HPT do not differ from those in subjects with hvpercalcemic HPT. 'ith regard to the other tw o groups of patients-those with hyperplastic and those with normal glands-the relation between glandular size and structure and symptoms is not clear. The glandular hvperplasia may be primary or secondary. Absence of signs of relapse is no proof of a primary glandular engagement. A slight or moderate hyperplasia secondan- to some unknown factor(s) would of course be in accord with the normocalcemic picture. The disease in the majority of the cases with normal glands has probably no parathyroid engagement. Of course, some mav have an incipient form of hyperplasia not vet discernible in the microscope. The others should be regarded as cases of "idiopathic hypercalciuria." Some max be renal calcium-loosers, whose parathvroids, for unknown reasons, do not react wvith secondary hvperplasia. Others may be intestinal hyperabsorbers of calcium. None of these two categories naturally should benefit from parathyroid surgery. Of course, other pathogenetic mechanisms may also exist. References 1. Johansson H, Thoren L. WN'erner I. Grimelius L: Normocalcemic hyperparathyroidism, kidney stones, and idiopathic hvpercalciuria. Surgery 77:691-696, 1973 2. Grimelius L: A silver nitrate stain for a2 cells in human pancreatic islets. Acta Soc Med Ups 73:243-270. 1968 :3. Gilmour JR. Martin VJ: The weight of the parathyroid glands. Pathol Bacteriol
44:431-468. 1937
4. Alvervd A: Parathyroid glands in thyroid surgery. I. Anatom- of parathyroid glands. II. Postoperative hv-poparath\-roidism-identification and autotransplantation of parathyroid glands. Acta Chir Scand Suppl 389:1-120. 1968 5. Ejerblad S. Grimelius L. Johansson H. Werner I: Studies on the non-adenomatous glands in patients with a solitary adenoma. Ups J Med Sci 1975 (In press)
FCu 1-Parathyroid gland with slight hyperplasia (mean weight 60 mg). The dark chief cells predominate. Some partly fibrotic areas, mainty perivascular, are seen. This patient did not F 2-Parathyroid gland with slight hyperplasia (mean weight 65 mg). relapse. (H&E, x 120) Light chief cells predominate. This patient relapsed after operation. (H&E, x 30)
A
.547
* Fiu S-Nodular parathyroid gland of normal weight This patient relapsed after operation. (H&E, x 30) Fre 4-Fat-rich parathyroid gland of normal weight. Dark chief cells predominate. This patient did not relapse. (H&E, x 120)
Surgical exploration of the parathyroid glands was carried out in 84 patients who had recurrent kidney stones and serum calcium levels in the upper quartile and most of whom had hypercalciuria. Parathyroid adenoma(s) were found in 19 cases, hyperplasia in 39 cases, and normal parathyroid glands in 26 cases. Postoperatively, a clinical follow-up was carried out for 2 to 5 years. No relapse has occurred in the cases with adenoma(s) but did occur in 24% of the group with hyperplasia and in 48% of the group with normal glands. The histopathologic findings are described here, while the clinical results are given in another paper. The adenomas do not differ histologically from those giving rise to hypercalcemic hyperparathyroidism. The hyperplasia was of the chief cell type and was slight in most cases. The "normal" glands did not differ from other normal glands from euparathyroid subjects. There was no significant difference in weight and histopathologic appearance between the hyperplastic glands of patients who relapsed and those who did not. Nor did the normal glands of "cured" patients differ from those of patients with relapse. However, in both these groups, some histologic features seem to indicate a favorable outcome; in the group with hyperplasia, there were higher glandular and parenchymal cell weight as well as predominance of light chief cells and small fibrotic areas. In the normal group, higher number of argyrophil cells and small fibrotic areas also seem to implicate a better prognosis. (Am J Pathol 83:475-484, 1976)
IN A PREVIOUS PAPER. Johansson et al.' described the outcome after parathxroid surgery^ of 84 patients who had had recurrent kidney stones and were suspected to have normocalcemic hyperparathyroidism. On the basis of glandular weight and histopathologic findings, the patients could be separated into three groups: those with parathvroid adenoma(s), those with hyperplasia, and those with normal glands. The best clinical results were obtained in the patients with adenomas, among whom there were no recurrences in a 2- to 5-year follow-up period; the least favorable results were in the group with normal glands. In the present paper the pathology of the parath\vroid glands will be described in detail and the histopathologic findings related to the clinical course. From the Departments of Pathology. Surgery. and Intemal NIedicine. 1 ppsala U ni%ersitv Hospital. Uppsala, Svveden. Supported by Project B76-17X-04787-O1 from the Smedish MIedic-al Research Council and b\- the MIedical Research Board of the Ss-edish Life Insurance Company Accepted for publication February 5. 1976. Address reprint requests to Dr. L. Grimelius. Department of Pathology. PO Box o.53. S-751 22. Uppsala 1, Sseden. 475
476
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Materalsxa
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Meth
The biopsy material was from 84 patients, 29 women and 55 men. The age at operation varied from 20 to 75 years; 53 patients were below 50 years. All had a historv of kidney stones, and all had serum calcium level in the upper normal quartile. In 29 patients, occasional serum calcium values of 5.3 to 5.5 mEq/liter were observed. The majority of patients had hypercalciuria; about one-third showed slightlv elevated borderline values. For details see Johansson et al. All four glands were explored. Biopsies from at least two glands for preliminary histologic examination (frozen section) were taken. When the preliminary diagnosis was adenomas, the tumors were removed, always together with the largest nonadenomatous gland. When the diagnosis was hyperplasia, the three largest glands were removed. If the fourth gland was normal-sized, it was left intact; if it was enlarged, it was partly resected. When all glands looked normal-sized, the three largest were extirpated. C
Fm
All patients were followed postoperatively during 2 to 5 (mean value 3.5) vears with regard to clinical symptoms of kidney stone disease, serum calcium levels, and urinarv calcium excretion. In some patients the level of serum PTH was also determined pre- and postoperatively (see johansson et al.l). The parathyroid glands were weighed and, depending on their size, divided into suitable pieces. The tissue was fixed in neutral formalin, dehydrated, cleared, and embedded in paraffin. The nonadenomatous glands, primarily diagnosed as normal or hyperplastic, were sectioned throughout in series of five consecutive 5-p-thick sections, with intervals of 150 p between each series. The adenomas were sectioned in three to five series of five consecutive 5-pthick sections with intervals of 300 to 500 p between the series. The sections in the different series were stained with hematoxvlin and eosin, the van Gieson stain, periodic acid-Schiff stain (PAS) with and without previous diastase digestion, and with the Grimelius silver nitrate stain.2 The amount of adipose tissue and the frequency of the different parenchvmal cell types was semiquantitatively evaluated through microscopic examination of all the hematoxylin and eosin-stained sections of each gland. The results were expressed as percent fat tissue of the total gland volume and the cell types as percent of the total number of parenchymal cells. A rough estimation of the parenchyma cell weight in the nonadenomatous glands was also made using the formula advised by Gilnour and Martin:3 (l.lxy)/(110 - 0.2z + 0.002yz), where x = total weight of the gland, y and z = percent parenchymal and fat tissue, respectively. The specific gravity of the fat tissue was taken as 0.9 and for remaining tissue as 1.1. The diagnosis of hyperplasia was primarily based on a mean glandular weight greater than 50 mg but the definitive diagnosis was based on parenchvma cell weight. The upper border value was 38 (mean weight + approximately 2 SD) according to Gilmour and Martin.'
Results Ademims
A solitary adenoma was found in 17 patients; in 2 there were two adenomas. All these patients were postoperatively free from relapse of
Vol. 83, No. 3 June 1976
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477
Table 1 -Sex Distribution
Patients with Adenomas(s) Cured Relapsed Hyperplastic glands Cu red Relapsed "Normal" glands Cu red Relapsed Total
M
F
8 0
11 0
25 6
4
8 8 55
6
4 4
29
The subgrouping is related to the pathologic diagnosis of the glands and the follow-up results.
kidnev stone symptoms (Table 1). Regarding sex and age of the patients at the operation, see Tables 1 and 2. The mean weight and range of the adenomas are given in Table 3. In eleven of the tumors a remnant of "normal" gland tissue was seen outside the connective tissue capsule. In thirteen adenomas there was a solid arrangement of the parenchymal cells together with varying amounts of acinar and pseudoacinar structures. Six adenomas consisted of two or more parenchvmal cell nodules surrounded bv connective tissue. In the remaining two tumors there were some solid parts, some nodules. In seven adenomas there was a predominance of dark chief cells, in six, a predominance of light chief cells, and in six, there was a fairly even distribution between dark and light chief cells (Table 4). In most adenomas, some oxvphil and transitional oxyphil cells were seen, and in one adenoma these cell tvpes predominated. Nuclear polvmorphism occurred in 3 cases. In all adenomas the majority of parenchymal cells contained PASpositive diastase-digestible substance (glycogen) (Table 5). The frequency of argyrophil cells varied (Table 6). In two solid adenomas, some inTable 2-Age of the Patients at Operation Patients with Mean age (yrs) Adenoma(s) Cured 51.2 Relapsed Hyperplastic glands Cured 51.3 Relapsed 43.3 "Normal" glands Cured 41.1 52.7 Relapsed For subgroups, see Table 1.
Range (yrs) 38-68
46-59 28-65 28-55
48-64
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GRIMELIUS ET AL
Table 3-Mean Weights and Range of Adenomas(s) and Glands
Patients with
N
Mean weight (mg)
Range (mg)
19 0
306
100-850
29 10
74 60
57-105 55-64
14 12
32
13-56 30-50
Adenoma(s)
Cured Relapsed Hyperplastic glands Cured Relapsed "Normal" glands
Cured Relapsed For subgroups, see Table 1.
-
41
flammator- cells wvere seen; in one of them small groups of lymphocytes occurred, in the other leukocvtes and plasma cells were seen also. In a third adenoma there were some fibrotic areas. The size and the weight of the nonadenomatous glands wvere all within normal limits as defined by Gilmour and Martin 3 and Alveryd.4 The dark chief cells predominated in almost all these glands. Hprsc
Glands
In 39 cases the parathyroid glands were classified as hyperplastic. Postoperatively, 10 of 39 patients have had recurrence of the kidney stone disease. Data of these patients regarding sex, age, and glandular w-eight and fat content are given in Tables 1-4 and 7. The glandular hyperplasia was of the chief cell type in all cases. The parenchy mal cells were arranged in cords and sheets separated by fat tissue and vessels or in more solid parts (Figures 1 and 2). In some glands, acinar and pseudoacinar structures were seen. Nodular cell arrangements were seen in one or two glands in about half the number of cases notwithstanding the subsequent outcome after surgery. The dark or light chief cells predominated in all the glands. A small Table 4-Mean Weight of the Parenchyma of the Glands Patients with Hyperplastic glands Cured Relapsed "Normal" glands Cured Relapsed
For subgroups, see Table 1.
Mean weight (mg)
Range
N
29 10
52 43
47-58 40-48
14 12
25 27
10-33 19-34
(mg)
Vol. 83, No. 3 June 1976
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Table 5-Semiquantitative Estimation of the Frequency of PAS-Positive Cells in Adenomas and Glands Percent PAS-positive cells of the total number of parenchymal cells
Patients with
N
< 10
11-40
41-60
61-90
> 90
Adenoma(s) Hyperplastic glands Cured Relapsed "Normal" glands Cured Relapsed
19
0
0
0
6
13
29 10
0 0
0 0
5 0
7 7
17 3
14
0 0
0 0
0 0
6 4
8 8
12
For each case, the mean value of the PAS-posifive cell type of the 3(1 ) glands was calculated.
number of oxyphil and transitional oxyphil cells were seen in most glands. A small percentage of transitional water clear cells were also seen in about one-third of the number of glands in the subgroup "cured," but only in a few - glands in the subgroup "relapsed." Regarding the prevalence of dark cells, PAS-positive, and argyrophil cells, see Tables 6, and 8. Small fibrotic areas mainly perivascularlv wvere seen in about one-third of the glands in the "cured" group but only occasionally in the relapsed group (Figure 1). 3,
Normal Glands
Normal histology was found in 26 cases. Postoperatively, 12 of 26 patients have shown relapse of urinarv tract stones. Data of these patients regarding sex, age, and glandular anatomv are given in Tables 1-4 and 7. Large glands often contained more fat than the small ones. The parenchvmal cell arrangements were similar to those in the hyperplastic glands. Nodular cell arrangements were seen in some parts in Table 6-Semiquantitative Estimation of the Frequency of Argyrophil Cells in Adenomas and Glands
Percent argyrophil cells of the total number of parenchymal cells Patientswith
N
< 10
11-40
41-60
61-90
> 90
4 2 7 Adenoma(s) 19 6 0 Hyperplastic glands 4 7 29 0 0 18 Cured 7 0 10 0 0 3 Relapsed "Normal" glands 14 2 7 5 0 0 Cured 12 0 7 5 0 0 Relapsed For each case the mean value of the argyrophil cell type of the 3(k) glands was calculated.
480
American Journal of Pathology
GRIMELIUS ET AL
Table 7-The Mean Values of the Amount of Fat Tissue of the Parathyroid Glands (percent of the glandular volume to the nearest 5%). Mean value Range N (%) (%) Patients with Hyperplastic glands Cured Relapsed "Normal" glands Cured Relapsed
29 10
30 15
15-50 10-20
14 12
30 40
5-70 30-50
For subgroups, see Table 1.
about one-third of the glands belonging to the subgroup "cured" and in about one-fourth of the glands in the other subgroup (Figures 3 and 4). The dark or light chief cells predominated. Also, a small number of oxyphil and transitional oxyphil cells were seen in most glands. Small groups of transitional water clear cells were seen in two of the three glands in a case belonging to the subgroup "cured." This cell type was not seen in the other subgroup. Regarding the frequency of dark cells, PASpositive, and argyrophil cells see Tables 5, 6, and 8. Small fibrotic areas were found in about one-third of the glands in the "cured" subgroup but only occasionally in the other. Discussion A strict differentiation between normal and slightly hyperplastic parathyroid glands is sometimes difficult or impossible. In the present studv the glands were primarily classified with regard to glandular weight. As the glandular weight in the same patient could differ from one gland to the other, the mean weights of the extirpated glands were used. The Table 8-Semiquantitative Estimation of the Frequency of Dark Chief Cells in Adenomas and Glands
Patients
N
Percent dark chief cells of the total number of parenchymal cells 41 -60 < 10 11-40 61-90 > 90
Adenoma(s) 19 2* 4 6 7 0 Hyperplastic glands Cured 7 12 29 0 10 0 Relapsed 10 0 0 4 6 0 "Normal" glands 14 1 Cured 3 4 0 6 12 4 Relapsed 0 2 6 0 For each case, the mean value of the cell type of the 3('h) glands was calculated. * In one of the two adenomas, the oxyphil and transitional oxyphil cells predominated.
Vol. 83, No. 3 June`1976
ADENOMAS IN HYPERPARATHYROIDISM
481
upper mean weight limit for normal glands was set to be 50 mg, as suggested by Gilmour and Martin3 and Alveryd.' Most parathyroid glands contained fat tissue in varying amounts. Therefore, the parenchvmal cell weight should provide a more accurate comparison than the glandular weight. This parenchymal cell weight is, however, time-consuming to determine, and for practical reasons the diagnosis will usuallv be based on the glandular weight. In our study the parenchymal cell weight was calculated and the upper mean weight limit for normal glands was set to be 38 mg (Gilmour and Martin3). Five cases, originally classified as hyperplasia, had to be rereferred to the normals. The mean value of the parenchymal cell weights of the glands classified as normal in our study was slightly higher than that found in normal glands by Gilmour and Martin.3 The corresponding parenchymal cell weight for the hyperplastic glands was almost double that of the normal glands in spite of the fact that the difference in total weight was less. The majority of the subjects with hyperplasia were males. The postoperative follow-up results were remarkably better in the male group (Table 1). The striking difference indicates that a slight hyperplasia has a more severe clinical significance in the male and really means hyperparathyroidism. Even if there are no significant differences in the glandular weights and histopathologic findings between the "cured" and "relapse" subgroups, the following factors seem to be favorable for the outcome of surgery on hyperplastic parathyroid glands: higher glandular and parenchymal cell weight, predominance of light chief cells, and the occurrence of transitional water clear cells and small fibrotic areas. It is fair to assume that a higher glandular and parenchymal cell weight indicate a larger and even increased production of parathyroid hormone. The significance of the predominance of light chief cells and the occurrence of transitional water clear cells is not certain, but it may also indicate an increased endocrine activity. Nor in the normal group were there any significant differences in weights or histopathologic findings between the glands from those patients who relapsed and those who did not. However, some histologic factors seem to be favorable regarding the prognosis: the higher frequency of argyrophil cells and the occurrence of small fibrotic area(s). The pathogenesis of these fibrotic areas in hyperplastic as well as in "normal" glands is unclear. It may be that these areas are the sequel of an earlier inflammation, viz., "parathyroiditis." It is feasible that such an inflammation may turn out to be one cause of kidney stone disease by means of intermittent or transitory hyperparathyroidism.
GRIMELIUS ET AL
482
American Journal
of Pathology
No relapse occurred in the group of patients with parathyroid adenoma(s). It seems reasonable to assume that these neoplasms caused the symptoms of hyperparathyroidism (HPT). It is not clear why the adenomas caused normocalcemic HPT and not hypercalcemic HPT. It mav depend on a small amount of hormone being released from the neoplasm, or the hormone synthesized b- the neoplasm may have an abnormal
biologic activity. In an earlier investigation, Ejerblad et al.5 made a histopathologic study of parathyroid adenomas causing hypercalcemic HPT. They' also extirpated one of the nonadenomatous parathvroid glands which were examined in the same way. The histologic findings in both the adenomas and the nonadenomatous glands in their study were similar to ours, i.e., the adenomas and nonadenomatous glands in cases with normocalcemic HPT do not differ from those in subjects with hvpercalcemic HPT. 'ith regard to the other tw o groups of patients-those with hyperplastic and those with normal glands-the relation between glandular size and structure and symptoms is not clear. The glandular hvperplasia may be primary or secondary. Absence of signs of relapse is no proof of a primary glandular engagement. A slight or moderate hyperplasia secondan- to some unknown factor(s) would of course be in accord with the normocalcemic picture. The disease in the majority of the cases with normal glands has probably no parathyroid engagement. Of course, some mav have an incipient form of hyperplasia not vet discernible in the microscope. The others should be regarded as cases of "idiopathic hypercalciuria." Some max be renal calcium-loosers, whose parathvroids, for unknown reasons, do not react wvith secondary hvperplasia. Others may be intestinal hyperabsorbers of calcium. None of these two categories naturally should benefit from parathyroid surgery. Of course, other pathogenetic mechanisms may also exist. References 1. Johansson H, Thoren L. WN'erner I. Grimelius L: Normocalcemic hyperparathyroidism, kidney stones, and idiopathic hvpercalciuria. Surgery 77:691-696, 1973 2. Grimelius L: A silver nitrate stain for a2 cells in human pancreatic islets. Acta Soc Med Ups 73:243-270. 1968 :3. Gilmour JR. Martin VJ: The weight of the parathyroid glands. Pathol Bacteriol
44:431-468. 1937
4. Alvervd A: Parathyroid glands in thyroid surgery. I. Anatom- of parathyroid glands. II. Postoperative hv-poparath\-roidism-identification and autotransplantation of parathyroid glands. Acta Chir Scand Suppl 389:1-120. 1968 5. Ejerblad S. Grimelius L. Johansson H. Werner I: Studies on the non-adenomatous glands in patients with a solitary adenoma. Ups J Med Sci 1975 (In press)
FCu 1-Parathyroid gland with slight hyperplasia (mean weight 60 mg). The dark chief cells predominate. Some partly fibrotic areas, mainty perivascular, are seen. This patient did not F 2-Parathyroid gland with slight hyperplasia (mean weight 65 mg). relapse. (H&E, x 120) Light chief cells predominate. This patient relapsed after operation. (H&E, x 30)
A
.547
* Fiu S-Nodular parathyroid gland of normal weight This patient relapsed after operation. (H&E, x 30) Fre 4-Fat-rich parathyroid gland of normal weight. Dark chief cells predominate. This patient did not relapse. (H&E, x 120)
