Concurrence of hyperplasia and neoplasia of the parathyroid glands

Concurrence of Hyperplasia and Neoplasia of the Parathyroid Glands* ABNER GOLDEN, M .D ., JOHN J . CANARY, M .D .

and

DONALD M . KERWIN, M .D .f

Washington, D . C. RIOR to 1958, hyperparathyroidism was classified as primary when associated with morphologic findings of adenoma or generalized water-clear cell hyperplasia and secondary when manifested by chief cell hyperplasia . The description of primary chief cell hyperplasia [1] made it apparent that the differentiation of primary from secondary hyperplasia cannot be made on the basis of cell "type," but rests on thorough evaluation of historic and biochemical data . Adenomas (and carcinomas) have always been considered primary phenomena . The recent report of a functioning adenoma developing in a patient with chronic renal disease and secondary parathyroid hyperplasia ("tertiary hyperparathyroidism") 12] adds a new complexity to the interpretation of parathyroid disease . Our experience with a group of six patients who exemplified a diversity of situations in which hyperplasia and neoplasia coexisted prompted this report . Two of our patients had long standing primary renal disease with secondary hyperparathyroidism . Late in their course, hypercalcemia developed and both were found to have a parathyroid adenoma with concomitant hyperplasia of the other glands . A third patient followed an apparently similar course . In one patient who had primary hyperparathyroidisin due to a large adenoma, renal insufficiency developed, and, at the time of surgery, a concurrent secondary parathyroid hyperplasia was found . Two other patients had primary hyperplasia of the parathyroid glands . In one of these patients multiple adenomatous nodules developed, in the other adenocarcinoma .

CASE REPORTS

P

CASE I .

This twenty-six year old housewife (P . W .) died during her third admission to Georgetown University Hospital . Her past history revealed that she had had enuresis until the age of thirteen . She was catheterized for urine specimens on several occasions at that time. Because of emotional difficulties, she was under the care of a psychiatrist at age fifteen and again at age nineteen . The first clinically apparent episode of pyelonephritis occurred thirteen months prior to her first admission to this hospital and led to study at another hospital where she was found to be febrile and to have leukocytosis, pyuria and azotemia . Blood urea nitrogen levels ranged between 50 and 80 mg- per 100 ml . Her serum calcium at that time was 8 .5 mg . per 100 ml ., serum phosphorus 7 .1 mg . per 100 ml . She responded to treatment with antibiotics . One year later she was readmitted to the same hospital because of another episode of acute pyelonephritis . She was given antibiotics for a short period of time and discharged . She continued to have flank pain, anorexia and nausea, and a furuncle developed on the right labium majus . Fever and dysuria led to her admission to this institution . The patient was a pale, malnourished, chronically ill appearing white woman . Rectal temperature was 102°F . The blood leukocyte count was 16,000 per cu . mm ., the hematocrit 23 volumes per cent . Urinalysis revealed fixed low specific gravity, a moderate amount of protein, numerous leukocytes, some white cell clumps and hyaline and granular casts . Roentgenograms of the chest and abdomen were noncontributory . The blood urea nitrogen was 170 mg . per 100 ml ., carbon dioxide combining power 13 .8 and chlorides 111 mEq . per L. Serum sodium and potassium levels were normal . Serum uric acid was 12 mg . per 100 ml . Sensm calcium was 10 .9 mg . per 100 ml ., high in relation to the serum phosphorus which was 9 .5 mg . per 100 ml .

* From the Departments of Pathology and Medicine, Georgetown University Medical Center, Washington, D . C . This study was aided in part by Grants AM-05602, AM-02935, AM-06496, TI-AM-5041 from the National Institute of Arthritis and Metabolic Disease of the National Institutes of Health, and a Clinical Research Facility Grant of the National Institutes of Health . Manuscript received May 26, 1964 . t Present Address : Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. 562

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Case t . A, right superior parathyroid gland and surrounding thyroid tissue . Note sharply demarcated adenoma and adjacent pale hyperplastic tissue . B, histologic appearance of adenoma . This lesion was composed of solid sheets of dart, chief cells . C, histologic appearance of a hyperplastic gland . Note increased cellularity and ahscuce of stromal fat . t), higher magnification of hyperplastic gland . Note trahecular arrangement of light chief cells . I Ten ato :ylin a ,,,I eosin stain, original magnification X 70 (C) ; X 180 (H and D) . 1''IG . T .

Treatment with two courses of peritoneal dialysis and broad-spectrum antibiotics led to clinical improvement, with a fall in the blood urea nitrogen level to 40 mg . per 100 ml . She was discharged on a regimen consisting of a 40 gm . protein diet, antibiotics and sodium bicarbonate, 35 to 40 mEq . per day orally. Pedal edema, increased weakness and dyspnea on exertion developed four months later . Several episodes of acute pain with erythema and swelling of the great toes had occurred during this four month period . She was admitted for the second time because of edema and dyspnea . Evidence of a pleural effusion was found on the right . The blood urea nitrogen had risen to 350 mg . per 100 ml . The carbon dioxide combining power was 9 .9 mEq . per L ., potassium 5 .7, chlorides 111 and sodium 143 mEq . per L . Hemodialysis was instituted, and there was a rapid response in symptoms and biochemical abnor. The blood urea nitrogen level was reduced to malities vor . 38, APRIL 1965

35 mg . per 100 ml . . serum electrolytes were normal and serum uric acid decreased from 11 .5 to 6 mg . per 100 ml . The patient was discharged on a 20 gm . protein diet but was readmitted for the last time six days later because of severe postural hypotension . Crinalysis revealed a specific gravity of 1 .01[1 and pH 6-5 . There was 1 .5 gin. of protein present per 24 hours, with 10 to 20 red blood cells and 15 to 2(1 white blood cells per high power field . The blood urea nitrogen was 150 mg . per 100 ml ., carbon dioxide combining power 12 mEq . per L ., chlorides 114, potassium 6 and sodium 143 mEq . per L . The serum calcium was found to he 11 .5 and phosphorus 12 .1 mg . per 101) ml . X-ray studies revealed marked demineralization of the lateral third of the clavicles bilaterally . 'there was demineralization of the skeletal system generally, with a granular appearance of the skull and subperiosteal resorption of the carpal phalange, . Eilnts obtained



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six months earlier had been interpreted as being within normal limits . Uremia became progressively severe, and death occurred a month after admission . At autopsy, three parathyroid glands were identified . (Fig . 1 .) The right superior parathyroid gland measured 2 .0 by 1 .5 cm . in greatest diameter . Its capsule was smooth . On cut surface, most of this gland was occupied by a homogeneous, soft greyish tan tissue surrounded on one margin by pale greyish white tissue which was sharply demarcated from the main mass . The histologic appearance was that of an adenoma composed of a virtually solid sheet of darkstaining chief cells with moderately large uniform oval nuclei, Moderate numbers of delicate blood vessels were present . The surrounding rim of tissue was composed of hyperplastic parathyroid tissue with a predominance of light chief cells but with moderate numbers of oxyphil cells . This tissue was remarkable in that it showed considerable interstitial fibrosis and hyalinization with focal atrophy of cellular elements . The two other parathyroid glands measured 1 .2 by 0 .5 and 1 .0 by 0 .5 cm . in greatest diameter. They were reddish tan in color and uniformly smooth on cut section . Histologically, these glands showed striking hypercellularity, with a virtual absence of fat. The cells were arranged in a trabecular or acinar pattern with occasional small cyst formation . The predominant cell was the light chief cell although many darker chief cells and oxyphil cells were also present . A few water-clear cells were seen . The kidneys weighed 25 and 40 gm . The cortical surfaces were coarsely nodular with deep scars . The cut sections showed only a small rim of renal tissue without demarcation of cortex and medulla . The calyces, pelves and ureters were not remarkable and no stones were encountered . The histologic appearance indicated massive destruction of the renal parenchyma by chronic pyelonephritis . Most glomeruli appeared completely hyalinized or showed periglomerular fibrosis . In most areas the tubules were atrophic and the interstitium showed striking fibrosis . Many chronic inflammatory cells were present . Numerous deposits of calcium were encountered not only in the tubular lumens but also in tubular epithelial cells and within glomerular structures . An occasional nephron composed of a glomerulus and its tubular structures was encountered within the fat tissue of the pelvis. Sections of multiple bones showed osteitis fibrosa varying in degree from moderate to severe . Sections near a pathologic fracture of the clavicle showed almost complete replacement of bony structures by loose fibrous tissue containing many nodules of osteoclastic cells . A section of rib showed evidence of mild osteomalacia superimposed upon the picture of osteitis fibrosa . The myocardium showed calcification of an occasional solitary muscle fiber . The remaining organs showed no evidence of abnormal calcification . Other

findings included a right temporal cerebral hemorrhage with rupture into the ventricular system, and pulmonary edema . The final anatomic diagnoses were uremia (clinical) ; chronic pyelonephritis, severe ; ?congenital renal hypoplasia ; adenoma of right superior parathyroid gland ; hyperplasia of two parathyroid glands ; osteitis fibrosa generalisata, severe, with pathologic fracture of left clavicle and mild superimposed osteomalacia ; nephrocalcinosis ; cerebral hemorrhage, right temporal lobe ; pulmonary edema and ascites .

Summary ;

This twenty-six year old patient

with symptoms suggesting urinary tract disease prior to puberty presented evidence of pyelonephritis with azotemia and mild hypocalcemia nineteen months prior to death . Biochemical findings compatible with hyperparathyroidism, i .e ., hypercalcemia in the presence of hyperphosphatemia, were noted thirteen months later at the time of her first admission to this hospital . X-ray evidence of bone changes of hyperparathyroidism developed during the last six months of life . The diagnosis of autonomous hyperparathyroidism rested upon the demonstration of persistent hypercalcemia with progressively severe renal insufficiency. The morphologic findings in this patient point to renal disease as the initial lesion . Kidneys of such small size indicate severe pyelonephritis during childhood and possibly the presence of a congenital hypoplasia . The occasional nephrons completely free in fat tissue suggest failure of development of some of the fetal lobules . The striking enlargement of the parathyroid glands also points to long-standing renal disease . The adenoma of the right superior gland was surrounded by a prominent rim of hyperplastic tissue . It was composed of dark chief cells, in contrast to the predominantly light chief cell and oxvphil pattern of the hyperplastic glands . The presence of significant hyperparathyroidism was indicated by the extensive bone disease and moderate nephrocalcinosis . The clinical and morphologic findings in this patient indicate primary renal disease of long duration, secondary hyperplasia of the parathyroid glands and subsequent development of an autonomous adenoma with manifestations of hyperparathyroidism . CASE n. A thirty-seven year old white male teacher (J. L .) was admitted to Georgetown University Hospital for the second time for the management of uremia and a severe neuromuscular disorder characterized as the Guillain-Barre syndrome . He had

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TASTE I LABORATORY DATA

Date

Serum Calcium (-g /100 m1 .)

Serum I i

Calcium Excretion (mg./24 hr .)

Phosphorus

(mg ./100 MI .)

Phosphorus Clearance

C'reatinine Clearance (nil . /inin .)

(MI. /Min,) I

5,8/63 6,110/63 8/1 1,63 8/6/63 8/15/63 9/6/63 9/7/63 9/8/63 9/9/63 9/10/63 9/15/63 9/16/63 9/1

8 .5 8 .0 8 .2 8 .9 10 .0 10 .0 11 .3 11 .8 12 .0 11 .8 12 .0 11 .3 11 .8

12 .0 9 .0 7 .0 6 .1 7 .0 5 .0 8 .3 7 .0 7 .5 7 .2 7 .0 8 .3 7 .7

63

9/18/63 9/19/63 9/21/63

9/25/63 10/1 /63 10/20,63

I 108 120 110

) 9

I

12 13 12

Surgery 9 .2 9 .5 9 .5 9 .7 9 .2 9 .5

7 .8 8 .0 6 .5 5 .8 5 .0 6 .7

been admitted four months earlier because of complaints of lower abdominal pain, nausea, vomiting and weakness of one week's duration . Other complaints were weight loss, pruritus of approximately one and a half month's duration and malaise of four months' duration . There was a history of difficulty with voiding dating to early childhood, and proteinuria had been present since the age of eleven following an episode of hentaturia . During the course of his first admission to this hospital, cystoscopy disclosed a stricture of the neck of the bladder . This was thought to be congenital . A left retrograde pyelogram revealed a very small left kidney ; no nephrocalcinosis was evident on roentgenograms . The vital signs were within normal limits . A uremic odor was noted and the mucous membranes were pale . Blood studies revealed a nolmocytic, normochromic anemia with a hematocrit of 23 volumes per cent . '1he white blood cell count and differential were normal . Urine specific gravities ranged between 1 .009 and 1 .013 with 4+ proteinuria. Protein excretion averaged 3 .0 gm . per day . A few white blood cells and occasional hyaline and granular casts were seen in the urinary sediment . During the course of the first admission the blood urea nitrogen level fell from 300 mg . per 100 ml . on admission to 70 mg . per 100 ml . at the time of discharge . Serum sodium levels prior to sodium supplementation averaged 125 mEq . per L . Therapy consisted of intermittent peritoneal VOL . 38, APRIL 1965

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48 36 48 49 38 45

0 .1 0 .5 5 4 4 8

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dialysis, institution of a 30 gm . protein diet with sodium supplementation, and antibiotic therapy . The symptoms subsided gradually and the patient was prepared for discharge . However, there was sudden onset of a progressive weakness of the legs and upper extremities . Roentgenograms of the skull and an electroencephalogram did not reveal any abnormalities . The cerebral spinal fluid protein varied between 200 and 400 mg . per 100 ml ., pressure, respiratory dynamics and sugar were all within normal limits . Serologic examination of the blood and spinal fluid was within normal limits . The patient was discharged after stabilization of the neurologic defects and when renal function appeared constant . During the course of this admission, serum calcium was determined on two occasions with values of 8 .0 and 8 .5 mg . per 100 ml . being obtained at a time when serum phosphorus levels were 9 .0 and 12 .0 mg . per 100 ml ., respectively . The patient was readmitted one week later . 'The blood urea nitrogen level had risen to 100 mg . per 100 ml ., the serum calcium level was 8 .9 mg . per 100 ml . and the serum phosphorus level 6 .8 mg . per 100 ml . During the next three weeks . serum calcium levels rose to 10 .1 and 10 .8 mg . per 100 ml . while serum phosphorus levels fell to 7 .0 and then to 5 .3 mg . per 100 ml . During this period the patient was maintained on a constant low protein, high sodium diet and no phosphorus-depleting agents were given . The

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Case u . A, external appearance of three parathyroid glands and biopsy specimen of left inferior gland . B, cut surfaces of upper glands . Arrow points to encapsulated nodule in left superior gland . C and E, photomicrographs of hyperplastic gland, showing absence of fat and rich vascular pattern . D, low power view of adenoma consisting of densely packed light chief cells surrounded by fibrous capsule. F, high power view of adenoma . flematoxylin and eosin stain, original magnification X 70 (C and D), X 180 (E and F). FIG . 2 .

blood urea nitrogen level fell from 160 to 90 mg . per 100 ml . A week later, the serum calcium level rose to 11 .3 mg . per 100 ml . while the serum phosphorus was 8 .0 mg . per 100 ml . On seven subsequent occasions serum calcium levels ranged from 11 .2 to 12 .5 mg . per 100 ml ., serum phosphorus from 5 .0 to 8 .0 mg . per 100 ml . Serum total proteins during this period were normal . Calcium excretions ranged from 109 to 122 mg . per 24 hours, while the patient received a

daily calcium intake of 150 mg . Creatinine clearance were 12 to 15 ml . per minute . Serum alkaline phosphatase averaged 5 .5 Bodansky units. Roentgenograms of the skull, hands, spine and ribs did not reveal any changes of osteitis fibrosis generalisata . The sequential changes in serum calcium and phosphorus, 24-hour urinary calcium excretion, phosphorus clearance and creatinine clearance are shown in Table r . Because of the consistent hyperAMERICAN JOURNAL OF MEDICINE



Parathyroid Hyperplasia and Ncoplasia-Golden et al. calcentia, relative hyperphosphaturia with reduced glomerular filtration rate and the relative hypercalciuria, surgical exploration was performed . The left and right superior and the right inferior parathyroid glands were removed . Their respective measurements were 1 .5 by 1 .0 by 0 .6 cm ., 1 .1 by L0 by 0 .5 crn ., and 1 .1 by 0 .8 by 0.5 cm . Seventy per cent of the left inferior gland was removed and this specimen measured 0 .8 by 0 .7 by 0 .4 cm . All glands were tan-brown, both externally and on cut section . 7 hey presented a homogeneous appearance with the exception of the left superior gland which contained an encapsulated nodule measuring 0 .8 by 0 .5 by 0 .4 cm . within its substance . Histologic examination (Fig . 2) demonstrated all glands to be composed of solidly packed sheets of light chief cells, many of which showed signs of vacuolization . Focal collections of oxyphil cells were seen . In some areas the monotony of the pattern was interrupted by follicular and acinar formations . The nodule in the left superior gland was completely surrounded by a thick fibrous capsule which was focally calcified . It was composed of an essentially homogeneous sheet of light chief cells with absence of adipose tissue . The cellular pattern did not differ significantly from some areas of the hyperplastic glands .

Summary :

This thirty-seven year old patient

had strong evidence by history of early obstruction of the bladder neck and acquired renal disease . He entered the hospital with azotemia, mild hepocalcemia and hyperphosphatemia . Over the course of several months the serum calcium rose to hypercalcemic levels in the presence of relative hypercalciuria and hyperphosphaturia . These findings indicated the development of autonomous parathyroid hyperfunetion, and surgery was performed . Three parathyroid glands and a portion of the fourth were removed . They were all enlarged, with histologic findings of diffuse hyperplasia . Light chief cells predominated, but groups of oxyphil cells were also present . The left superior gland contained an encapsulated nodule with a uniform and homogeneous distribution of light chief cells . Although the cellular pattern was similar to some areas of the hyperplastic glands, ' was interpreted as an adenoma . CASE in . This forty-nine year old housewife (C . C .) complained of diffuse skeletal pains for ten years . She had had nocturia for seven years, recurrent episodes of acute arthritis for five years, a 10 pound weight loss, and anorexia and weakness for two months prior to admission . "There was a family history of gout. On examination, the patient was obese ; vital signs

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were normal . Band keratopathy was not present . Urinalysis revealed cloudy yellow urine with specific gravities averaging 1 .010, acid reaction and 3 to 4 white cells per high power field . The packed blood cell volume was 27 per cent, the, hemoglobin 8 .9 gull . per 100 ml . The white blood cell count and differential were normal . The blood urea nitrogen was 94 mg . per 100 mt_. the serum uric acid 10 .3 mg . per 100 Oil . Serum alkaline phosphatase activity ranged from 8 .3 to 9 .3 Bodansky units . Serum total proteins were 7 .2 gm . per 100 ml . with normal albumin and globulin levels . The fasting blood sugar level was at the upper limits of normal and the 2 hour postprandial sugar level was 190 mg . per 100 ml . The set urn calcium on admission was 11 Ing . per 100 ml ., the serum phosphorus 7 .2 mg . per 100 ml . Roentgenograms revealed minimal diffuse demineralization in the ribs and clavicles . There was thickening of the calvarium with spotty areas of demineralization producing a granular appearance . There was an osteolytic lesion in the distal portion of the medial border of the proximal phalanx of the first digit of the left foot which was interpreted as compatible with gout . The patient was treated conservatively for renal insufficiency . Thirty days after admission the serum calcium level had fallen to 10 .5 mg . per 100 Oil ., the phosphorus level had risen to 9 .2 mg . per 100 ml ., and the blood urea nitrogen level had risen to 147 mg . per 100 ml . Severe abdominal pain developed on the fortieth hospital day ; the patient became confused and lethargic, with abdominal distention and rigidity . Serum amylase was found to be markedly increased between 1,000 and 1,200 units per 100 ml . Renal insufficiency worsened, with urinary output falling to less than 100 ml . per 24 hours on the day prior to death . The serum calcium level on that day fell to 9 .2 mg . per 100 ml . while the serum phosphorus level rose to 12 mg . per 100 ml . Unresponsive hypotensinn developed and the patient died quietly . At autopsy, four parathyroid glands were identified . (Fig . 3 .) the largest of these measured 2 .0 by 1 .0 by 0 .8 cm . Its capsule was smooth and on cut section it appeared greyish brown in color and homogeneous in consistency . Histologically, this gland was composed predominantly of a large nodule of closely packed light chief cells with large, hyperchromatic nuclei lying within a well vascularized stroma, The cells were arranged in cords and clusters, and only rare fat cells were seen . Bordering this nodule was a crescent shaped rim of parathyroid tissue composed of chief cells and water-clear Cells with an occasional small nodule of large oxyphilie cells . Approximately 30 per cent of this rim of tissue was composed of adipose tissue . The remaining parathyroid glands measured 0-9 by 0 .5 by 0 .3 cm ., M by 0 .4 by 0 .3 cm . and 0 .7 by 0 .4 by 0 .3 cm . They were all reddish tan . Histologically, they showed an increase in cellularity, although some fat cells remained . The predominant cell was the

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Pte . 3 . Case in . A, margin of encapsulated adenoma in largest gland. Note small quantity of normal appearing parathyroid tissue to left of adenoma . B, higher magnification of adenoma, showing trabecular arrangement of light chief cells . C, nodule of water-clear cells in hyperplastic gland . There is an over-all decrease in stromal fat . D, nodule of oxyphil cells in hyperplastic gland . Hematoxylin and eosin stain, original magnification X 70 (A and C), X 180 (B and D.) water-clear cell which at times appeared in hyperplastic nodules . There were also multiple nodules of large cells with eosinophilic cytoplasm and small pyknotic nuclei . The kidneys weighed 80 and 75 gm . The surfaces were finely granular and the cut sections showed poor demarcation of cortex and medulla together with an increase in peripelvic fat . No stones were present . Histologic examination revealed advanced chronic pyelonephritis with obliteration and scarring of many glomeruli and tubules . Periglomerular fibrosis was prominent- Some areas of tubular hypertrophy and dilatation were noted . In addition to these findings, many glomeruli showed striking focal nodular hyaline deposits and other glomeruli showed basement membrane thickening of the stalk area . There was no evidence of nephrocalcinosis . Sections of bone revealed numerous focal areas of osteoclastic resorption with slight associated fibrosis of adjacent marrow areas . This process involved only a

small proportion of the trabeculae seen . Most of the trabeculae, however, showed broad osteoid seams on their surfaces. Other findings included an acute pancreatitis with surrounding fat necrosis, myocardial hypertrophy (400 gm .), pulmonary edema, atelectasis and bronchiectasis, fatty metamorphosis of the liver and obesity . The final anatomic diagnoses were uremia (clinical) ; chronic pyelonephritis ; diabetic glomerulosclerosis ; parathyroid adenoma, with hyperplasia of remaining parathyroid glands ; acute pancreatitis ; mild osteitis fibrosa and osteomalacia ; myocardial hypertrophy ; pulmonary edema, atelectasis, bronchiectasis ; fatty metamorphosis of liver ; obesity .

Summary : This forty-nine year old housewife with a long history compatible with gouty arthritis was admitted with azotemia . She was found to be hypercalcemic in the presence of AMERICAN JOURNAL OF MEDICINE



Parathyroid Hyperplasia and lNeoplasia-Golden et al . hyperphosphatetnia . The serum calcium level fell to normal with progressive hyperphosphatemia and renal failure . Acute pancreatitis developed terminally without accompanying hypocalcemia . The autopsy findings of severe chronic pyelonephritis without nephrocalcinosis and the very mild degree of osteitis fibrosa generalisata indicate primary renal disease with secondary parathyroid hyperplasia . The largest parathyroid gland consisted of an encapsulated mass of uniform light chief cells with a rim of tissue showing the same variation in cell type and pattern as the other hyperplastic glands . As in the first two patients, an adenoma appeared to develop in the course of secondary hvperplasia, its autonomous function indicated by absolute hypercalcemia in the presence of azotemia and hyperphosphatemia . CASE . IV . This thirty-six year old housewife (P . M .) had had recurrent bilateral renal stones for twenty-six years . Ilypercalcemia of 11 to 12 Prig . per 100 ml, had been noted intermittently during many previous hospital admissions . Pyelonephritis developed at an early age, and at thirty-three a nephrectomy was performed because of obstruction and infection . She had had acute arthritic episodes for seven years associated with hyperuricemia . Gout had been documented in her family . A neurologic disorder compatible with the Charcot-Marie-Tooth syndrome had been present for twenty-five years, and a similar disorder had developed in her eleven year old son . Recurrent episodes of abdominal pain had occurred during the previous four years . Vital signs were normal . Band keratopathy was observed bilaterally . There was atrophy of the thenar, hypothenar and interossei muscle groups bilaterally . Pes cavus was present with hammer toes, distal weakness, absent reflexes and mild sensory deficit . The hematocrit was 36 per cent, with a normal white blood cell count and differential . Urinalysis revealed a specific gravity averaging 1 .010, acid reaction, negative protein and normal sediment . Blood urea nitrogen ranged between 25 and 35 mg . per 100 ml . Serum total proteins were 6 .8 and 7 .0 gm . per 100 ml ., with normal albumin and globulin . Serum electrophoresis was normal on several occasions . Serum uric acid levels were 8 .4 and 7 .6 mg. per 100 ml . Serum calcium varied between 12 .9 and 15 .0 mg. per 100 ml ., serum phosphorus between 3 .1 and 3 .3 mg . per 100 ml . The glomerular filtration rate averaged 30 nil . per minute ; the phosphorus clearance was 19 ml . per minute . On a caleuim intake of 150 mg . the 24 hour urinary calcium excretion was 225 mg . Roentgenograms revealed marked calcification of the pancreas, and minimal bony changes compatible with osteitis fibro:,a of the skull and hands .

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Two right parathyroid glands were rcutoved at surgical exploration . One of the paraGc roil glands measured 0 .8 by 0 .7 by 0 .4 cm . and was reddish brown . Only a I mm . fragment of the second gland removed was available for morphologic stuck . Oil histologic examination (trig . 4) both the intact gland and the fragment of the second gland showed dhstine t hypercellularity composed of water-clear cells and a paucity of fat. The cells were arranged in solid masses divided only by thin connective tissue septutns . No changes in serum calcium or phosphorus levels NN-era noted following surgery, and the patient was readmitted for further study one month later . The glomerular filtration rate had improved . averaging 55 nil . per minute . Serum calcium levels were unchanged ; urinary calcium was somewhat lower . 'I' he administration of cortisone for ten days did not alter serum or urinary calcium levels . although the glomerular filtration rates had increased further to 70 ml . per minute . The serum calcium level fell to normal for four days and again for one week following the administration of phosphorus . At the crud of the second period of phosphorus administration . a second neck exploration was carried out . Nodularity of the right thyroid lobe was noted and resected, but no further parathyroid tissue was identified . "1`he left superior parathyroid was identified . It was much smaller than the previously removed right glands . and a biopsy specimen was taken . A large mass in the superior left mediastinum was discovered and removed . Serum calcium levels dropped promptly during the postoperative period . The mass removed from the left supeior mediastinum measured 4 .5 by 2 .9 by 2_3 cm . Its external surface was lobulated and covered by dense connective tissue . The cut surface appeared similarly lobulated and was pale brownish pink . Many small cysts varying in size from 0.1 to 0 .3 cm . were noted . 1 tistologic examination (Fig . 4) revealed a nodular mass composed of densely packed cells which were separated by irregular connective tissue hands . An occasional glandular pattern was noted . Although in moat areas rite cells had a uniform appearance of dark chief cells, several nodular areas composed almost exclusively of oxyphil cells also participated in the tumor mass . The parathyroid tissue identified adjacent to the upper pole of the left lobe of the thyroid gland measured 1 mm . in diameter . It was found to be approximately 50 per cent adipose tissue . 'file parathyroid cells were predominantly small dark-staining chief cells arranged in a trabecular pattern . Summary : This thirty-six year old woman had had recurrent bilateral renal scones for twenty-six years, and intermittent hypercalcemia . Pyelonephritis had developed, and a nephrcetomy was performed at age thirty-three . She also suffered from gout, recurrent panercatitis and the Charcot-Marie=booth syndrome .



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Case Iv . A, external view of large mediastinal parathyroid adenoma removed at second surgical exploration . B and 1), histologic appearance of adenoma . C, low power view of hyperplastic gland removed at first operation. Note marked decrease in stromal fat and hypercellularity . E, fragment of second hyperplastic gland removed at first operation. F, biopsy specimen of left upper gland at second operation . The distribution of cells and stromal fat appears normal . Ilematoxylin and eosin stain, original magnification X 70 (B, C, E and F), X 180 (D) . FIG . 4.

Persistent hypercalcemia (13 to 15 mg. per 100 ml .), normal phosphatemia, reduced renal function, hypercalciuria and hyperphosphaturia led to exploratory surgery . Two parathyroid

glands were removed which showed waterclear cell hyperplasia . Serum calcium and phosphorus levels remained unchanged, although there was some improvement in the AMERICAN JOURNAL OF MEDICINE



Parathyroid Hyperplasia and glomerular filtration rate . A second exploratory procedure revealed a 4 .3 by 2 .9 by 2 .3 cut . parathyroid tumor in the upper mediastinum ; serum calcium levels dropped promptly following its removal . A biopsy fragment of the fourth parathyroid gland appeared normal . The findings indicate primary hyperparathyroidism of many years' duration due to a mediastiual adenoma . Moderate renal insufficiency related to recurrent nephrolithiasis may have stimulated secondary hyperplasia of the non-neoplastic glands . CASE V . In this thirty-nine year old housewife (I . R .), illness began eight to ten months prior to her admission to Georgetown University Hospital . Nausea, anorexia and intermittent vomiting had led to two prior hospitalizations . No abnormal physical findings had been noted and urinalyses, blood counts and blood urea nitrogen determinations were within normal limits . Roentgenograms of the upper and lower gastrointestinal tract were interpreted as being within normal limits. Lethargy, weakness, irritability and burning and redness of the eyes, with excessive lacrimation, led to her final admission . Polyuria and polydipsia had also been noted . The packed red blood cell volume was 35 per cent ; white blood cell count and differential were normal . The urinary specific gravity was 1 .005 with an acid pH . Urine output ranged from 3,000 to 5,500 ml . per day . The blood urea nitrogen was 23 mg . per 100 ml . The patient's symptoms progressed, with increasing lethargy, and she became semicomatose after eight days in the hospital . Lumbar puncture at that time showed an elevated initial pressure of 220 mm . of water, but normal respiratory dynamics, protein and sugar content . Roentgenograms of the skull were interpreted as being compatible with Paget's disease, multiple myeloma or hyperparathyroidism . Serum calcium was 20 mg . per 100 ml . and serum phosphorus 4 .2 rng . per 100 ml . The blood urea nitrogen level had risen to 60 mg . per 100 ml . Hypotension developed on the ninth day and was unresponsive to therapy with pressor amines . The patient was transferred to Georgetown University Hospital for emergency therapy . Her coma was unresponsive to all stimuli . Body temperature was 102'r . Bilateral band keratopathy was noted, with calcification of the tarsal plates . An electrocardiogram revealed a very short S-T segment . Despite emergency measures, the patient died in ventricular fibrillation a half hour after transfer . Laboratory studies reported postmortem revealed a white blood cell count of 30,100 per cu . min ., a hematocrit of 46 per cent and a blood urea nitrogen level of 140 mg. per 100 ml . Serum calcium was 21 .6 mg . per 100 ml ., phosphorus 6 .2 mg . per 100 ml ., with normal serum proteins . Roentgenograms, obtained from the refer-

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ring hospital and others taken postmortem . demonstrated marked alterations in the architecture of all bones . particularly of the skull . pelvis. ribs, hands and distal thirds of the clavicles, which were CunsisLent with osteitis fibrosa generalisata . 'I he chr i . 1 1 1 n , revealed a bilateral hazy iniiltrale . At autopsy, a nodular elongated tumor mns> measuring 8 .0 by 3 .5 by 1 .5 cm . and weighing 19 gin . teas found adjacent to the lower pole of the I,-h . Iol e of the thyroid gland . The tumor was rightly adherent to the thyroid gland at multiple sites . On cut weiion it was composed of multiple nodules appearing white to pale yellow . Histologic examination (Fig . 5) revealed nodules of parathyroid tissue, at times conglomerate . The cells were arranged in rather solid sheets but at times showed a somewhat irabenilar partem . A striking feature was perivascular palisading of tumor cells . The cells appeared unusually large . with moderately dark-staining cytoplasm and large oval hyper chromatic and pleornorphic nuclei . 'Ifie individual nodules appeared to be surrounded by dense fibrous connective tissue, but in several areas Minor tissue invaded lymphatic: tissue, and in one area was seer to penetrate the capsule of the thyroid gland . Blood vessel invasion was noted . Calcification of the stroma was striking . Two other parathyroid glands uric identihed . These measured 1 .0 by 0 .5 and 0 .9 by 0 .5 cm . in greatest diameter, and had a combined weight of 100 mg . Histologically, they appeared markedly hypercellular, with only rare fat cells . The parathyroid cells were arranged at times in an acinar pattern and at times in a trabecular pattern . The cells appeared quite large but not as large as those of the tumor . '[fit, cytoplasm was paler and the nuclei were smaller and more uniform than those of the tumor . The kidneys weighed 220 gm . each and shtowed no gross scarring. There was extensive calcification of glomerular tufts, renal tubular cells and interstitium as well as calcification of vascular walls . The only other significant morphologic finding teas the presence of an occasional hyalinized glomerttho and occasional focal interstitial fibrosis . 'I here was metastatic calcification in most organs . This was most striking in the walls of arteries and arterioles but was also present to a remarkable degree in the pulmonary alveolar septums and in the lamina propria of the gastric mucosa . Sections of bone showed an advanced degree of osteitis fibrosa generalisata with most of the marrow spaces replaced by dense fibrous tissue and accumulations of osteoclasts and very irregular bony trabeculae . Other findings included cerebral edema and an adenoma measuring 2 .3 c ur . i n diameter in the cortex of the left adrenal gland . The final anatomic diagnoses were adenocarcinoma of left lower parathyroid gland ; hyperplasia of two parathyroid glands ; severe osteitis fibrosa generalisata ; massive metastatic calcification of visceral

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Fin . 5 . Case V . A, autopsy specimen showing thyroid, larynx and trachea (at left) . Note lobulated mass arising from lrft lower parathyroid region. Two other parathyroid glands are indicated by arrows . B, histologic appearance of adenocarcioonta of left lower parathyroid gland- Note prominent dark nuclei and rich vascular stroma . C, invasion of cervical lymph node by masses of tumor cells . D, mass of tumor cells lying within lumen of small blood vessel . E and F, low and high power view of hyprrplastic gland . Note absence of fat and solid or cord-like arrangement of light chief cells . Hematoxylin and eosin stain, original magnification X 70 (E), X 180 (B, C and F), X 360 (D) .

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Parathyroid Hyperplasia and Ncoplasia- Golden el al . organs ; ncphrocalcinosis, severe ; cerebral edema ; cortical adenoma of left adrenal gland . Summary : This thirty-nine year old woman had symptoms of hyperparathyroidisin for eight to ten months . Marked hypercalcemia was followed by coma and shock . Death resulted from ventricular fibrillation . The absence of significant renal disease other than nephrocalcinosis, the severe osteitis fibrosa generalisata and extensive metastatic calcification all point to primary hyperparathyroidism due to generalized primary hyperplasia . Adenocarcinoma, manifested by invasion of thyroid, lymphoid tissue and blood vessels, appears to have developed in a hyperplastic gland . CASE vi . This sixty-three year old woman (C . Y .) had been followed at Georgetown University Hospital for many years . She had been blind since an episode of acute streptococcal pharyngitis at the age of eleven . Hypertension was diagnosed at age forty, and she had intermittent evidence of cardiac insufficiency . Chronic renal infection became apparent seven years later . She was admitted for study eleven years prior to her final hospitalization . The blood pressure ranged from 150 to 190 man . Hg systolic and 80 to 100 mm . Hg diastolic . Minimal cardiac enlargement was present, and electrocardiograms revealed mild left ventricular strain . There were diffuse retinal changes compatible with a healed choriorctinitis and vision was limited to minimal light perception . There was no band keratopathy . The hematocrit, white blood cell count and differential were within normal limits . Urinalysis showed specific gravities between 1 .010 and 1 .018 . Proteinuria (1 4- to 2-I-) was present in most speciatens . The urine was acid and was sterile on culture . Phenolsulfonphthalcin excretion was 15 per cent in 1 .5 minutes, 40 per cent in 2 hours . Roentgenograms revealed a normal skeleton, except for demineralization of the lumbar spine ; there was bilateral nephrocalcinosis . Serum calcium ranged from 11 .5 to 12 .0 ang, per 100 ml ., serum phosphorus from 2 .8 to 3 .2 mg . per 100 ml . Urinary calcium excretion with the patient on an unrestricted diet, varied between 150 arid 200 Ing . per 24 hours . The blood urea nitrogen was 15 to 25 mg . per 100 ml ., and creatinine clearances averaged 45 to 50 Led . per minute . The patient was discharged without specific therapy and was seen intermittently in the Outpatient Clinic . Progressive loss of hearing was attributed to otossderosis. An elevated fasting blood sugar and abnormal glucose tolerance curve was noted three years before her final admission, and she was treated with tolbutamid . She continued to show mild hypercalcemia and normal serum phosphorus levels . She was admitted for further study . The blood pressure was unchanged ; electrocardiograms revealed

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left ventricular hypertrophy . Rocntgenograms rrvealed a norrnal skull . demineralization of the( lumbar spine and changes in the fingers compatible with minimal subperiosteal resorption . Blood counts and urinalyses were within normal limits except for urine specific gravity of 1 .004 to 1 .008 . The blood urea nitrogen was 25 mg . per 100 in] . Serum calcium remained between 11 .3 and 11 .5 ang . per 1017 ml . arid serum phosphorus between 3 .1 and 3 .2 mg . per 10o ml . Glomerular filtration rates averaged 30 ml . per minute with phosphorus clearances of 12 ml . per minute . Urinary calcium excretion with the patient on a calcium intake of 150 mg . was 108 mg . per 24 hours . Aluminum hydroxide gel was administered for ten days while she was taking a 151) mg . calcium diet . The serum calcium level rose to 12 .7 mg . per 100 ml . while the serum phosphorus level fell to 25 mg . per 100 ml . Serum total proteins were repeatedly normal . Serum calcium was unaltered during a her, day administration of cortisone, 150 tog . daily . A biopsy specimen of the iliac crest revealed changes compatible with ostcids fibrosa generalisata. Surgical exploration of the neck was performed during the seventh week of hospitalization . Two tumor-like masses were removed from tissue adjacent to the upper poles of the thyroid gland . One of these was an irregularly shaped hemorrhagic and greyish mass measuring 1 .5 by 0 .6 by 0 .2 em . On cut section it revealed multiple pale white, well circumscribed nodules measuring op to 3 mm, in diameter . The second mass measured 2 .5 by 0 .8 by 0L7 cm . and was also seen on cut section to be composed of multiple nodules of pale white tissue measuring up to 3 mm . in greatest diameter . 'I he histologic appearance of these two masses showed marked variability . (,Fig . 0 .) In most areas the tissue had the appearance of hyperplastic parathyroid tissue composed predominantly of light chief cells . The organization of the cells varied, but in many areas had a distinctly follicular pattern with frequent formation of small cysts . Very little fat was present . The most distinguishing feature of these two masses, however, was the presence of rnultiplr small and larg e nodules within the hyperplastic tissue . One nodule was composed entirely of water-clear cells in an acinar arrangement ; other nodules were composed of virtually solid sheets of small dark straining chief cells . Biopsy specimens were obtained front the remaining two parathyroid glands . 'They showed a moderate increase in cellularity composed-l predominantly of chief cells although both oxyphil and water-clear cells were seen . There was a tendency toward papillary configuration although most areas maintained an acinar pattern . Summary : This sixty-three year old woman had had hypertension for twenty-three years, hypercalcemia and nephrocalcinosis for eleven years . Renal function was only moderately

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Parathyroid Hyperplasia and Neoplasia-Golden et al .

FIG. 6 . Case vr. A, cut surfaces of both upper parathyroid glands removed at surgery . Note multiple circumscribed nodules and dark meaty appearance of surrounding tissue. R, over-all appearance of excised parathyroid tissue, showing solid masses of light chief cells . There is no stromal fat . C, encapsulated nodule of dark chief cells . D, encapsulated nodule of water-clear cells displaying an alveolar pattern . Hematoxylin and eosin stain X 7 0 (B, C and D) .

impaired despite evidence of recurrent pyelonephritis . The upper parathyroid glands were markedly enlarged and showed both diffuse chief cell hyperplasia and multiple nodules some of which were encapsulated . The lower glands revealed less striking hyperplasia . The findings in this patient are best interpreted as primary parathyroid hyperplasia with

the development of multiple nodules strongly suggestive of adenomasCOMMENT S The coexistence of parathyroid hyperplasia and neoplasia raises interesting and important questions concerning the relationship between the two . Is their occurrence together merely a AMERICAN JOURNAL OF MEDICINE



Parathyroid Hyperplasia and Neoplasia- Golden et al . coincidence, or can the two lesions be causally and functionally related? The study of our patients leads to the conclusion that in all six instances hvperplasia and neoplasia were related to each other, although the nature of this relationship varied . Our observations also suggest that in certain patients the concurrence of hyperplasia and neoplasia can be recognized on the basis of biochemical manifestations . Primary Renal Disease with Secondary Parathyroid Hyperplasia and Subsequent Autonomous Adenoma Formation . This sequence of events is strongly indicated by the data in Cases t and tt . Both patients had early evidence of renal disease with functional impairment . In both, azotcmia was at first associated with hyperphosphatemia and normal or low serum calcium levels . Hypercalcemia developed subsequently, and both were found to have adenomas as well as generalized hyperplasia of the parathyroid glands . Although the data in Case in are not as conclusive, they suggest that renal disease was primary. This patient was found to have severe chronic pyelonephritis with superimposed diabetic nephropathy, uremia, relatively mild osteitis fibrosa generalisata and hypercalcemia, and showed no evidence of nephrocalcinosis or metastatic calcification . A similar course of events is indicated in the patient discussed in The Case Records of the Massachusetts General Hospital 121 . The term "tertiary hyperparathyroidism," introduced by St . Goar, appears to be a useful designation . The most significant finding in this group of patients was the development of hypercalcemia in a setting of chronic renal disease with azotemia and hyperphosphatemia . The occurrence of hypercalcemia as a manifestation of secondary hyperplasia of the parathyroids has been a subject of extensive discussion in the literature . Our experience, as well as that of David et al . [3J, Albright et al . [4] and Howard [5J indicates that true lrypercalcemia does not occur in uncomplicated secondary hyperparathyroid, ism, no matter how long the duration, or how severe the degree of osteitis fibrosa ,generalisata . A critical review of reports of hypercalcemia in rectal insufficiency reveals only two instances in which secondary hyperplasia could have been responsible [6,7j, and in these the possibility of primary hyperplasia cannot be dismissed . The stimulus for parathyroid hyperplasia in renal insufficiency is believed to be the lowered serum level of ionized calcium, although some

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evidence suggests a role of hyperphusphatemia unrelated to calcium level. The stimulus to increased parathormone secretion should no longer exist once the serum level of ionized calcium has been corrected . The development of true hyperealcemia is evidence of autonomous parathyroid hormone secretion and cannot be attributed to homeostatic mechanisms [~51 . The development of neoplasia following prolonged stimulation to hyperplasia raises the question of the role of hvperplasia in the evolution of certain ncoplastic lesions . Although no conclusions as to a direct causal relationship can be drawn from our patients, it is well to point out that certain analogous situations occur, particularly in the endocrine organs . 'The well known production in experimental animals of granulosa cell tumors in ovaries transplanted to the spleen [8l might be cited, as can the production of autonomous functional pituitary tumors in nice following excision or ablation of target organs [9 1 . It has been demonstrated that in women with estrogen-producing ovarian tumors the incidence of enrlometrial carcinoma is increased 1101, and the appearance of pituitary tumors in patients with Cushing's syndrome who are subjected to bilateral adrenalectonry [11] might be related to increased stimulus for ACTH secretion . Primary Parathyroid Adenoma Leading to Renal Insufficiency and Senjndory Hyperplasa of Remaining Parathyroid Glands . Secretion of parathyroid hormone by primary adenomas is autonomous, i .e ., unrelated to the needs of the body . Although little is known of the quantitative aspects of hormone secretion by an adenoma, it is possible that the development of renal disease with azotemia and other metabolic changes might create need for still greater hormone secretion . A truly autonomous adenoma would not respond to this stimulus, and the remaining parathyroid glands could undergo hyperplasia . There have been at least six reports of the development of secondary parathyroid hyperplasia in patients with primary hyperparathyroid ism due to adenoma This sequence of events is suggested in our Case iv . This patient had well documented hyperparathyroidism, with the development of mild azotcmia . At surgery she was found to have a large adenoma and hyperplasia of two other glands . The exact stimulus to hypcrplasia, however, was not apparent. Despite azotemia, the serum calcium levels remained elevated . Serum



576

Parathyroid Hyperplasia and Neoplasia-Golden et al . '1AELE IT MORPHOLOGIC FINDINGS

Case No .

Neoplasm

1

Encapsulated adenoma 2 .0 by 1 .5 cm . ; dark chief cell

2 3

4 5 6

Surrounding Parathyroid Tissue

Hyperplastic Glands

Light chief cells and moderate ' 1 .2 by 0 .5 cm ., 1 .0 by 0 .5 cm . ; light number of oxyphil cells chief cells, some dark chief and oxyphil cells Encapsulated adenoma 0.8 by I Light chief cells, with some 1 .1 by 1 .0 by 0 .5 cm . ; 0 .8 by 0 .7 by 0 .5 by 0 .4 cm. ; light chief oxyphil cells 0 .4 cm . ; light chief cells, with some cell oxyphil cells Encapsulated adenoma 2 .0 by Chief and water-clear cells, 0.9 by 0.5 by 0.3 cm ., 0 .6 by 0 .4 by 1 .0 by 0 .8 cm . ; light chief with oxyphil nodules 0 .3 cm ., 0 .7 by 0 .4 by 0 .3 cm. ; cells water-clear cells and oxyphil nodules Encapsulated adenoma 4.5 by 0.8 by 0 .7 by 0 .4 cm . ; biopsy of 2 .9 by 2 .3 cm . ; dark chief second gland ; water-clear cells cells Invasive adenocarcinoma 8 .0 1 .0 by 0.5 cm., 0 .9 by 0 .5 cm . ; light by 3 .5 by 1 .5 cm . chief cells Both upper glands 2.5 by 0 .8 Light chief cells Biopsies ; light chief cells, with some by 0 .7 cm ., 1 .5 by 0 .6 by water-clear and oxyphil cells 0.2 em . ; multiple encapsulated dark chief cell nodules ; 1 encapsulated water-clear nodule

total proteins and phosphate were normal and, although she demonstrated pancreatic calcification, there was no evidence of malabsorption . The possibility remains that in some patients a factor other than hypocalcemia or hyperphosphatemia can stimulate parathyroid hyperplasia . It is tempting to think that hyperplasia can be a reflection of an attempt to lower serum calcium levels by secretion of the hormone calciotonin [17], but if this mechanism were to obtain, one would expect to see secondary hyperplasia more frequently in patients with primary hyperparathyroidism due to adenoma . Primary Parathyroid Hyperplasia with Subsequent Parathyroid Neoplasia . In Case v manifestations

of severe hyperparathyroidism developed over a period of several months preceding death . Evidence of severe impairment of renal function was lacking until the last three days of life . At autopsy the patient was found to have a generalized hyperplasia of the parathyroid glands and a carcinoma of the left lower gland showing extensive local infiltration and vascular invasion . She had advanced osteitis fibrosa generalisata, massive metastatic calcification of visceral organs and nephrocalcinosis . There was no underlying renal disease . In Case vi significant and persistent hypercalcemia was found in the presence of normal

serum phosphate levels . Although the patient had a history of recurrent pyelonephritis and showed evidence of renal functional impairment, she was never azotemic . At surgery, she was found to have two tumor-like parathyroid masses adjacent to the upper poles of the thyroid as well as hyperplasia of the lower glands . The upper glands revealed multiple nodules of varying cytologic characteristics, several of which were sharply demarcated and suggestive of true adenoma formation . The term "primary hyperplasia" implies the absence of a known stimulus to increased growth and function . Primary hyperplasia appears to represent an autonomous lesion with parathyroid hormone secretion uninfluenced by serum calcium or phosphorus levels [5] . Although the development of neoplasia in glands showing primary hyperplasia is of both theoretic and practical interest, our limited observations do not permit broad conclusions as to the relationship between the two lesions . MORPHOLOGIC CONSIDERATIONS

Criteria for the morphologic diagnosis of parathyroid abnormalities assumed major importance in this study . The findings and the basis of their interpretation in each patient have been detailed in the case summaries . AMERICAN

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Parathyroid Hyperplasia The two histologic features most relied upon in the diagnosis of parathyroid adenoma are a true rim of normal parathyroid tissue outside the tumor capsule and the presence of another parathyroid gland that is normal [78] . It is apparent from our study that the non-neoplastic glands may he hyperplastic, as may be the parathyroid tissue immediately surrounding a tumor . In five of our six patients there were distinct histologic differences between the lesions interpreted as neoplastic and the hyperplastic glands . These differences lay in cytologic characteristics, arrangement of cells and stromal pattern. The neoplasms, with one exception, showed homogeneity of cell type, a uniform and frequently solid pattern of cell distribution and total absence of stromal fat . The hyperplastic glands displayed some mixture of cell types with the predominant cell differing from that of the neoplastic lesion . The adenomas in Cases i and in showed rims of non-neoplastic tissue outside the capsule . In Case n there was distinct encapsulation of the adenoma, although its cytologic pattern differed only slightly from the surrounding parathyroid tissue . The diagnosis of an adenoma in Case iv is indicated by its unusual size (4 .5 by ? 9 by 2,3 cur .) as well as its histologic characteristics . The adenocarcinoma in Case v showed invasion of the thyroid gland, lymphoid tissue and blood vessels . In Case vi there were multiple nodules arising in taro large hyperplastic glands . Several of these were encapsulated, uniform in cell type and arrangement and were considered neoplastic. The morphologic findings in our patients are summarized in Table it_ The findings in our patients point to new problems for internist, surgeon and pathologist when patients with hyperparathyroidism undergo exploration . Removal and morphologic identification of an adenoma can no longer be assumed to be curative, since the patient may still be suffering from hyperparathyroidism due to underlying primary hyperplasia, or the adenoma may have developed in the course of long-standing hyperplasia secondary to chronic renal disease . Conversely, the removal of one or two hyperpiastic glands does not rule out the presence of an adenoma . It becomes incumbent upon the surgeon to explore and observe all four normal parathyroid areas, regardless of the findings in any one . Finally, our observations vor . 3 8 .

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give new emphasis to the need for thorough evaluation of all historic and laboratory data prior to surgical exploration . Of particular importance is the search for evidence of developing autonomous parathvroid function in patients with chronic renal disease and secondary hyperparathyroidism . St7MSMARv The concurrence of parathyroid hyperplasia and neoplasia in a group of six patients is reported . Two patients had long-standing renal disease with azotcmia and hyperphosphatemia . In both hypercalcemia developed while they were under observation and they were found to have parathyroid adenomas as well as hyperplasia of the other glands . A third patient followed an apparently similar course . One patient with primary hyperparathyroidism due to a large mediastinal adenoma displayed hyperplasia of other glands in association with moderate renal insufficiency . Two patients with primary generalized parathyroid hyperplasia were found to have superimposed neoplastic lesions : multiple adenomatous nodules in one_, adenocarcinoma in the other . These observations add new dimensions to the diagnosis and therapy of parathyroid disorders . They indicate the necessity of examining all four parathyroid areas at time of surgery . They also emphasize that hypercalcemia developing in patients with chronic renal disease is a manifestation of autonomous parathyroid function . Acknowledgment : We wish to express our appreciation to Dr . Laurence H . Kyle for his advice and interest during these studies and to Drs . Robert .1 . Coffey, George E . Schreiner and John F . Maher for their contribution to the care and study of these patients . REFERENCES 1 . Core . O., KE.YNes, W . M . . Rvrn, S . 1 . And mAn, B . Primary chief-cell hyperplasia

2.

CASTtLof the parathyroid ,glands : a new entity in the surgery of hyperparathyroidism . Ann . Sarg., 148 : 375, 1958 . Case records of the Massachusetts General Hospital, No. 29-1963. firm Erzgland J . Med ., 268 :943, 1963 .

3.

4.

5.

DAVID, N . J ., VERNER, J . V . and F Nary, F . L. The diagnostic spectrum of hypercalcemia . Case reports and discussion . Ann . J. Med ., 33 : 88, 1962 . AI .BRIcHT, F ., BAIRD, P . C . . Cope . O . and BcnomBeac, E . Studies on the physiology of the parathyroid g lands . sv . Renal complications of hyperparathyroidism . Am . J . A1 . Sc ., 187 ; 49, 1934. HOWARD, J, E . The clinical picture of hyperpara-



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thyroidism. In : The Parathyroids, p . 460, Edited by Creep, R . 0 . and Talmage, R . V. Springfield, III ., 1961 . Charles C Thomas . 6 . SVMrH, F . S . and GOLDMAN, L . Renal rickets with metastatic calcification and parathyroid dysfunction . Am . J. Dir. Child ., 48 : 596, 1934 . 7 . Clinicopathologic Conference . Am . J. Med ., 21 : 117, 1956, 8 . Lt, M . H . and GARDNER, W . U. Further studies on the pathogenesis of ovarian tumors in mice. Cancer Res., 9 : 35, 1949 . 9 . FURTHI, J . Experimental pituitary tumors . Recent Progr . Hormone Res., 11 : 221, 1955 . 10 . GREENE, J . W., JR. Feminizing mesenchymomas (granulosa-cell and theca-cell tumors) with associated endometrial carcinoma . Am. J. Ob.rt . & Gynee ., 74 : 31, 1957 . 11 . NELSON, D. H ., MEAKIN, J . W . and 1'IIORN, G . W . ACTH-producing pituitary tumors following adrenalectomy for Cushing's syndrome . Ann . Int . Med., 52 : 560, 1960 . 12 . SoFFER, L. J. and COHN, C . Primary and secondary

13 .

14 .

15 .

16 .

17 .

18 .

hyperparathyroidism . Arch . Int . Med ., 71 : 630, 1943 . DOWNS, R . S . and ScorT, V . Hypcrparathyroidism with adenoma causing renal failure and secondary hyperparathyroidism . Report of a case. Arch . Int . Med., 67 : 658, 1941, JOHNSON, J, W ., JR . Primary hyperparathyroidism with extensive renal calcification and secondary hyperplasia of parathyroids ; report of cases. Am . J. Path ., 15 : 111, 1939 . DENT, C . E, and HoDSoN, C . J . Generalized softening of the bones due to metabolic causes ; radiologic changes associated with certain metabolic bone diseases . Brit. J. Radiol., 27 : 605, 1954 . LEE, C . M ., .JR ., MCELIIINNEY, W . T . and GALL, E . A . Unusual manifestations of parathyroid adenoma . Arch. Surg ., 71 : 475, 1955 . Copp, D. H . and CHENEV, B . A. Calciotonin-a hormone from the parathyroid which lowers the calcium level of the blood . Nature, 193 : 381, 1962 . ROTH, S . .1 Pathology of the parathyroids in hyperparathyroidism . Arch . Path, . 73 : 495 . 1962 .

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