Elderly Females, Two of Whom Had Each One Parathyroid Tumor, While the Third Had Two Distinct Tumors of Parathyroid Tissue

Home , Osteitis fibrosa cystica, Osteomyelitis

FIBROCYSTIC DISEASE OF THE BONES ASSOCIATED WITH TUMOR OF A PARATHYROID GLAND *

REPORT OF A CASE

RAYmOND S. ROSEDALE, M.D. (From 1K Pathological Laboratory of the Buffalo City Hospal, and the University of Buffalo, Buffalo, N. Y.) Generalized fibrocystic disease of bone was first described as generalized osteitis fibrosa cystica by von Recklinghausen' in a Fest- schrift to Virchow in I89I. The earliest references we have to tumor of the parathyroid glands are those of De Santi2 in I900 and Ben- jamins 3 published in 1902; bone disease was not mentioned. Erd- heim4 in 1903, Hulst I in 1904, and MacCailum6 in I905, also each reported a case without associated bone disease. Askanazy7 reported finding a parathyroid tumor in association with osteitis deformans in I904, and von Vereb6ly 8 reported a case of parathyroid tumor with bone changes in 1907. Weichselbaum9 described a parathyroid tumor in I906 without associated bone changes. Erdheim 10 described three cases of osteomalacia with parathyroid enlargement in 1907. Thompson and Harris 11 described a similar case in I9o8. Seven cases of parathyroid tumor without mention of bone changes were collected and one of his own added by Da Costa 12 in I909. Bauer 13 in I9II reported a case of adenoma of the parathyroid in a 45 year old woman with a moderate degree of osteomalacia. In I9I3 Molineus14 described osteomalacia in three elderly females, two of whom had each one parathyroid tumor, while the third had two distinct tumors of parathyroid tissue. Har- bitz 15 in I9I5 noted the "relationship between enlargement of the parathyroid glands, rickets and other diseases affecting the bones." Tumors of the parathyroid gland have been reported as coincident findings in several diseases. Bergstrand 16 in I92I reported tumor of the glands in nephritis, tetany, epilepsy, eclampsia and osteomalacia. * This case was reported in abstract before the Buffalo Pathological Society on February I9, 1932. Received for publication April 5, 1932. 745 746 ROSDALE In So cases of nephritis he found one or more enlarged parathyroid glands. Other authors, induding MacCallum, have reported the coincidence of parathyroid enlargement with nephritis. Hoffheinz 7 in1925 collected 45 cases of parathyroid tumors; in I7 of these there was an assocated generalized osteitis fibrosa cystica, 8 cases with osteomalacia, and 27 with various other bone diseases. The concept of the relation between tumors of the parathyroid gland and generalized fibrocystic disease has been n ging within the last few years Erdheim in I9I1 put forth the hypothesis that the enlargement of the gland was a compensatory effort to assist in replacing lost calcium to the bones. This theory held sway for many years. In 1923 Dawson and Struthers 9 stated that the glandular hyperplasia was an effort to prevent the ecessive excretion of lime salts and also control and prevent the development of an excess amount of guanidine, which was considered toxic. The first intimaton that hyperparathyroid function might be a cause of generalized fibrocystic disease of bones through withdrawal of calcium was in I915, when Schagenhaufer 2 advised parathyroidectomy in two cases of generalized fibrocystic disee associated with a parathyroid tumor: Maresch favored the procedure but Bauer rejected the proposal. In 1925 MandlP1 transplanted parathyroid tissue into a patient with generalized fibrocystic disese and the patient's condition became worse. He then removed the transplanted parathyroid tissue and a parathyroid tumor, and there was improvement of the fibrocystic diseae. Gold 2 performed a parathyroidectomy in 1927, with Simi- lar improvement of the patient's bone disease. Barr and his coworkers 2h a parallel case in1929. Since this time there have been reported 23 cases of generalized fibrocystic disease of bones asociated with parathyroid tumor, in each of which the tumor was removed, with subsequent improvement of the bone condition. Collip in I925 24 described blood calcium elevation after parathormone was injected in dogs, and also an increase in blood phosphorus in parathyroidectomized rabbits. Greenwald and Gross in I925,25 and again in 1926,E* showed that daily parathormone injection of ioo units in animals elevated the serum calcum and caused excretion of urine calciumandphosphorus, the former to as much as six times normal. Hunter and Aub 7 also FIBROCYSTIC DISEASE OF BONES 747 found the same hypercalcemia with increased calcum excretion in man in 1926. Albright, Bauer, Ropes and Aub28 have demonstrated a negative calcium bance in animals and man receiving parathormone injections. Finally, the disease picture, both gross and microscopic, of generalized fibrocystic disease of bones has been produced repeatedly by Jaffe, Bodansky and Blair,2' and also by Byrom working with Hunter and Turnbull.Y More recently Johnson and Wilder t reported that repeated injections of parathyroid extract produced in puppies and young rats uniform bone lesions characteristic of generalized fibrocystic disease of the bones, and conduded that the disease observed in man was due to an oversupply of parathyroid hormone with consequent loss of bone calcium. Thus the interrelationship of generalized fibrocystic disease of bone and hyperparathyroidism has gradually been established. We have found 3I reported cases of generalized fibrocystic disease of bones associated with enlargement of a parathyroid gland. Some of these were reported as hyperplasia, others as adenomas, and one as a malignant adenoma. All of these present definite clinical and laboratory data to establish further the causal relationship of these two conditions. One additional case is presented herewith. CASE REPORT Clinical History: D. S., age So years, white, female, married housewife, entered the Buffalo City Hospital April 9, 1931, complaining of muscle aches, fatigability, pain about the knee joints and lower part of the right tibia, and loss of use of the lower limbs because of weakness. As a young girl she had had a goitrous sweUling of the neck for which she was treated with iodine. Following this the swelling disappeared. At the age of 27 years she had a periapical tooth infection that left her with a condition that was termed chronic osteomyelitis; this resisted all ordinary attention, a sinus persisting until a radical surgical procedure caused it to heal after two years. Constipation had been obstinate for thirteen years. Seven years ago she had what was interpreted as sciatica, the pain being in both gluteal regions. For the past three years a sense of soreness was present in both heels; this was aggravated by weight-bearing. She had lost 7I lbs. in weight in this three year period, the former maxmum weight being i6o lbs. About three years prior to hospital admission she had had an attack of sharp, right upper quadrant pain with sudden onset and cessation, which was interpreted at the time as renal colic. For the last two years needle-like pain was experienced around the knees; for the past five months a pain was sensed over the lower third of the right tlbia. This, aggravated by motion, has been present constantly. She had been conscious of a firm swelling in the right thyroid region, and more recently a sense of tightness. There had been no dysphagia. Nervousness, force- 748 ROgv-nALE ful pulsation of the neck vessls, and a fine tremor had been present for three years. Aprecordial pain had been interpreted at one time aspericarditis. Night and day fiequency of urination was constant. The patient was an elderly, emaciated female with drawn and haggard fea- tun The bonyprominences andhollows were mared The skull was seemingly larg than normal in contrast with the face bones. There was a slight exoph- thalmos and a suggestion of nystagmus; the sclerae had an icteric tinge. The neck vessels pulsated forcibly; a tender firm nodule was palpble in the lower lateal portion of the right thyroid lobe. Most of the teeth wre missing; the few remaining onms we carious The heart was slightly enlarged to percusson, the left border measuri 8.5 cm- to left of the midine in the fifth intercostal space, and the right 3.5 to the right of the midline in the fourth interspace; there were two cardiac murmurs, a mitral systolic blow and a rough aortic systolic. Extra systoles were frequent The systolic blood pressure Was 122, and the diastolic 68. No arteriosclerosis was detected. The mus of the extrei- ties were atrophic, their tone poor. A slightly tender area was found over the lower third of the right tibia. The lc eal regions were tender. Pulse and respirations were normaL The temperature occsonally rose to 99.8 and io00 F. AU other points of the anainnesis were negative. Laboratory Studies: Red blood cel 2450,000; eMOglobin 58 per cent (Sahli); color index 1.2; white blood cells Io,Ioo; differtial normaL A series of blood calcium deteminations yielded I6.5, 13.82, I4.52 mg. pe Ioo cc. The blood phosphorus was 2.3 mg. per I00 cc. of blod. Urie: specific gravity anged constantly between Ioo6 and I013; albumin was I Plus to 4 Plus; rare granular cast. Bence-Jones protein action was positive on one occasion and negative on another. Basal metabolic rate was within normal limits. IThe X-ray revealed cystic areas in the ribs, clavide, lae, humii, tibiae and mandible, vacuolization of the skull and a generalized loss of density of all the bones. Biopsy m atl from the right tibia was obtained April i8, and was diag- nosed as fibrocystic disease of bone. On May I5, 193I, a tumor mass was roved from behind the right thyroid lobe. Local anesthesia was used. Following this the patient became stuporous with nervousness, apprension, cdonic twitchings of hand and face muscles, and could be aroused only by parathyroid and aldum therapy. The serum calcium determination on the same day, after 20 CC. of 5 per cent calcium chloride and 2 cc. parthormone was injected intraenously, was found to be 9.2 mg. per zOO cc. of blood With the onset of dyspnea, cyanosis and vasomotor collape, an acute urinary suppression su v A blood urea detrmination showed 68.5 mg. per zOO cc. of blood. Death folowed four days after operation. Autopsy was refused. BoNE BIOPSY The material received from biopsy* consisted of two fragments of bone each I ca. square and 3 mm. thick, and two bone fragments about 2 mm. in diameter, one minute piece of soft white tissue about I mm. m diameter, and some blood dot bulking about i cc. * The bone bios and th parthyroid ghn!d tumor wre sbmed by Dr. H. N. Kenweil and Dr. Pietro Banco of the Bufalo city HospitaL EIBROCYSTIC DISEASE OF BONES 749 The sections stained with hematoxylin and eosin exhibited strands of osteoblastic tissue running at irregular angles from the periphery inward, forming a totally irregular pattern with no osseous structures present The cells of the strands had a very scanty, faintly stining cytoplasm; their nudei tended to be round or oval, and had within them a deeply staining chromatin material within which darker granules were seen with the aid of the oil immersion objective. Some thin-walled vascular structures were found throughout the section. The above type of c yielded gradually by transition to larger paler cells with paler staining nudei, the cytoplasm being more abundant and of a granular nature. Adjacent to and between these latter cells a mature fibrous reticulum was noted in a back- ground of homogeneously light grayish pink vacuolation. Blood vessels in these latter areas were scarce, but here and there in the large vacuoles an isolated red blood cell was seen. In this and other sections multinudeated large cells were found scattered throughout the fields, but chiefly in and around the vascular, younger and more active appearing osteoblastic areas. These cells approximated i5 to 20 microns in diameter. The cytoplasm was stained a soft grayish pink and the nudei pinkish blue; these were round and oval and situated eccentrically, and had sharp out- lines. They contained mostly a nudeolus and in some cases many smal dark blue granules. The nudei approximated about 4 microns in dianeter. The greatest number of nudei counted in any one giant cell was 28; the least number was S. The cytoplasm of the multinudeated cells was irregularly and faintly outlined and within the cytoplasm of several of them fragments of red blood cells were seen. In another section of bone the osseous tissue had been partly re- placed by osteoid tissue stained a light pink, and in some places a deeper bluish pink The homogeneity of the osteoid tissue was broken only by iregularly situated elliptical clls in lacnae. These ells had scant cytoplasm and oval nudei with poorly staining chromatin materiaL Between the osteoid areas, and dipping into them in finger-like processes were groups of osteoblasts and fibrous tissue strands. At the periphery of the osteoid tissue the osteoblasts were larger thn elsewhere, the cytoplasm was dear and the nudei were stained a deep blue. The cells dose to the areas of osteoid tissue were larger and had more deeply staining chomai than those farther away. 750 7ROALE As before, multinudeated cells or osteodastomata were seen, but they were not so large as those previously descrbed, and they had a deeply stiningnudeus. They were concentrated here more on the inner (marrow) aspect of the osteoid tissue. Between the limiting membrane of the osteodastoma and the surrounding structure there was in many instances a dear area. One received the impression that the osteoclastic activity here was about two or three times that of the osteoblastic process. One cc. of a brownish red fluid was obtained from a cyst in the right tibia during the biopsy. Direct smnears of this showed an occasional Gram-positive short bacillus, thought to be contamina- tion. The Rivalta test was 4 plus. Cultures did not exhibit any bacterial growth Smears of the fluid stained with hematoxylin and eosin showed many normal a red blood cells, about five lymphocytes per high power field, and a rare three or four-lobed polymorphonudear neutrophilic leukocyte. In one field there was seen a fainDy pinkish gray, vacuolated, roughly circular "ghost" cell, which contained darker bluish pink, indistinctly outlined structures. This looked as though it might be a degenerated osteodast The tissue diagnosis was fibrocystic disease of bone.

PARATYROID TUMOR The nodule removed from the thyroid region was a piece of tissue that weighed 7 gm This was irregularly elongated and somewhat V-shaped. It measured 2 thugh its long diameter and 2.5 CM. across, and was dark brown in color. It appeared to be well en- Sections of the tumor stained with hematoxylin and eosin ex- hinbited a thin fibrous capsule from which bundles of connective tissue swept centripetally, septating the glandular parenchyma. A delicate fibrous reticulum supported the glandular cells These re- solved themselves into several types. There were lobules of brighter, pinker staining tissue which were found to be chiefly large poly- hedral cells, with a moderate deeply staining granular cytoplasm and oval nudei which were a light pinkrish blue with few granules. The cells had an alveolar arrangement in some fields, and the alveolar spaces contained a pinker staining, amorphous material. Scattered among these pale oxyphilic cells were basophilic or prncipal cells. IBROCYSTIC DISEASE OF BONES 75I1 These latter had slightly larger nudei which stained a purplsh blue and contained coarse granules. In one section basophilic cells formed alveoli containing an amorphous addophilic substance. The prin- cipal or basophilic cells were scanty in number and the cell membrane was not dearly seen. Occasionally an addophilic cell was seen among the nests of basophilic cells. An iron stain, using the Prussian blue reaction, showed some sall granules of black material in some of the connective tissue septae A fat stain (scarlach R) revealed some intercellular fat globules, mostly in a region of the chief cells, but also in some of thecllaries. Small, thin-walled capillaries were frequently seen among groups of cells. There was one field that showed cystic nge with a brownish staining pigment in the cystic areas and in the surrounding connective tissue structures. No mitoses were seen. Only two types of glandular cells were noted. No evidence of irregularity of the cellular proliferation was noted. The tissue diagnosis was adenomatous hypertrophy of a parathyroid gland, with cystic degeneration.

i. The literature concerning the development of the concept of the relation of genealized fibrocystic disease of bones to hyperparathyroidism has been reviewed. 2. A case of generalized fibrocystic disease of bone in corrlation with a tumor of parathyroid gland has been presented. The author is indebted to Dr. William F. Jacobs, Pathologist- in-Chief of the Buffalo City Hospital for the use of this material, and for his criticsm in its development. 752 ROSEDALE

REFERENCES I. von Reling , F. D. Die fibr6se oder deformierende Ostitis, die Osteom e und die osteoplastische Carzinose in ihren gegenseitigen Beziehungen Festschrift der Assistenten fUr R. Virchow, 189I, Berlin, Verlag von G. Reimer. Quoted by Hunter and Turnbull (Ref. 30). 2. De Santi. Inkrna. Zentralbi. f. Laryng. u. Rhin., I900. Quoted by Har- bitz (Ref. is). 3. Benjamins, C. E. Ueber die Glandulae parathyreoidea (Epithelk6rper- chen). Bejtr. s. path. Anal. u. s. alUg. PaIhol., 1902, 31, 143. 4. Erdheim, J. Zur normnalen und pathologischen Histologie der Glandula thyreoidea, parathyreoidea und Hypophysis. Bejir. z. path. Anat. u. z. aUg. Pat/ol., 1903, 33, 158. 5. Hulst, J. P. L. E;I Tumor der Glandular parathyreoidea. Centralbi. f. aUg. Palho. u. Path. Anal., 1905, z6, 103. Quoted by Hoffheinz (Ref. I 7). 6. MacCallum, W. G. Tumor of the parathyroid gland. Bull. Johns Hopkins Hosp., I905, I6, 87. 7. Askanazy, M. Ueber Ostitis deformans ohne osteoides gewebe. Arb. a. d. Palwlogssch-Anatomischen Institut su Tiibingen, I904,4, 398. Quoted by Harbitz (Ref. Ii). 8. von Verely, T. Beitrige zur Pathologie der branchialen Epithelk6rper- chen. Virdowws Arch. f. path. Anal., I906-07, 187, 80. 9. Weichselbaum. Ueber cin Adenom der Glandula parathyreoidea. Ver- hand. d. deutsch. path. Gesdlsch., 906, I0, 83. Quoted by Harbitz (Ref. I5) . io. Erdheim, J. Ueber Epithe}brerbefunde i Osteomaiaie. Sitzngsb. d. Akad. d. Wiss., Wi,90o7, ii6, pt 3,311. Quoted by Hunter and Turn- bl (Ref. 30). iI. Thompson, R L., and Harris, D. L. A consideration of the pathological histology of the parathyroid glandule, and a report of a parathyroid- like tumor. J. Med. Res., 1908, 19, 135. 12. Da Costa, J. C. Parathyroid tumors, with report of a case. Surg. Gynec. Obst., 19o9, 8, 32. 13. Bauer, T. Ueber das Verhalten der Epithelk6rperchen bei der Osteo- malacie. Frankfurt. Zlsckr. f. Path., rIgI, 7, 231. Bauer, T. As part of discussion of caghaufeJer's case (see Ref. 20). 14. Molineus. Ueber die Multiplen braunen Tumoren bei Osteomalaie. Arch. f. klin. Ckir., I913, 101, 333. 15. Harbitz, F. On tumors of the parathyroid glands. J. Med. Res., I9I5, 32, 36I. I6. Bergstrand, H. Parathyreoideastudien. II. Ueber Tumoren und hyper- plastische Zustinde der Nebenschilddriisen. Ada. med. Scandina., 19217 54, 539. (Abstr. J. A. M. A., 1921, 76, i8o7.) FIBROCYSTIC DISEASE OF BONES 753 17. Hoffheinz. (Yber Vergr6sserungen der Epithelk6rperchen bei Ostitis fibrosa und verwandten Krankheitsbildern. Virckws Arch.f. path. Anat., 1925, 256, 705. I8. Erdheim, J. Ueber denKalkgehalt des wachsenden Knochens und des Callus nach der Epithelkorperchenextirpation. Frankfurt. Ztsckr. f. Path., 1911, 7, 175. I9. Dawson, J. W., and Struthers, J. W. Generalized osteitis fibrosa with parathyroid tumor and metastatic calcification. Edinburgh M. J., 1923, 30,421. 20. Schlagenhaufer. Zwei F4il1e von Parathyreoideatumoren. Wien. klim. Wdmsckr., 1915, 28, 1362. 21. Mandl, F. Attempts to treat generalized fibrous osteitis by extirpation of a parathyroid tumor. Zentralb. f. Ckir., i926, 53, 260. (Abstr. J. A. M. A., 1926, 86, II04.) 22. Gold, H. Excision of parathyroid tumor in generaliz osteitis fibrosa. Wien. ed. Wc/nschr., 1927, 77, 1734. Quoted by Wilder, R. M. Wilder, R. M. Hyperparathyroidism; Tumor of the parathyroid glands associated with osteitis fibrosa. Endxrinology, 1929, 13, 231. 23. Barr, D. P., Bulger, H. A., and Dixon, H. H. Hyperparathyroidism. J. A. M. A., I929, 92, 951. 24. Collip, J. B. The parathyroid glands. Harvey Lectures, 1925-26,21, 113. 25. Greenwald, I., and Gross, J. The effect of the administration of a potent parathyroid extact upon the excretion of nitrogen, phosphorus, calcium and magnesium: Solubility of calcium phosphate in serum and patho- gens of tetany. J. Biol. Chcem., I925, 66, 217. 26. Greenwald, I., and Gross, J. The effect of long continued administration of parathyroid extract upon the excretion of phosphorus and calciun J. Bil. C/sm., 1926, 68, 325. 27. Hunter, D., and Aub, J. C. Lead studies. XV. The effect of the parathyroid hormone on the excretion of lead and of calcium in patients suf- fering from lead poisoning. Quart. J. Mcd., 1927, 20, 123. 28. Albright, F., Bauer, W., Ropes, M.. and Aub, J. C. Studies of caldum and phosphorus metabolism. IV. The effect of the parathyroid hormone. J. Clin. Investigation, 1929, 7, 139. 29. Jaffe, H. L., Bodansky, A., and Blair, J. E. Fibrous osteodystrophy (osteitis fibrosa) in experimental hyperparathyroidism of guinea pigs. Arc/. Path., 1931, II, 207. 30. Hunter, D., and Turnbull, H. M. Hyperparathyroidism: generalized osteitis fibrosa with observations upon the bones, the parathyroid tumours, and normal parathyroid glands. Brit. J. Surg., 1931, 19, 203. 3I. Johnson, J. L., and Wilder, R. M. Exprimental chronic hyperparathyroidism. I. Metabolism studies in man. Am. J. k. SC., 1931, I82, 800. DESCRIPTION OF PLATE

PL&in II8 FIG. I. Bone biopsy. Hnatoylin d osin stain. Hypehromatic osteo blasts are see at the edge of one island of osteoid tise. Osteoclastomata appear at the pecri y of anothr osteoid island. There is a oniderable degree of fibrous tissue between the osteoid structures. FIG. 2. Parathyroid tumor. FIG. 3. Parathyroid tumor. Hematoxylin and eosn stain. AMERIcA-N JOURNAL OF PATHOLOGY. VOL. VII PLE iI8

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