0021-972x/92/7502-0362$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society

Studies

in a Kindred

Vol. 75, No. 2 Printed in lJ.SA.

with

Parathyroid

Carcinoma

ELIZABETH A. STREETEN, LEE S. WEINSTEIN, JEFFREY A. NORTON, JOHN J. MULVIHILL, BEVERLY J. WHITE, EITAN FRIEDMAN, GITIE MARIA LUISA BRANDI, KAREN STEWART, MARK B. ZIMERING, ALLEN M. SPIEGEL, GERALD D. AURBACH, AND STEPHEN J. MARX

JAFFE,

Metabolic Diseases Branch and the Cytogenetics Unit, Laboratory of Chemical Biology (B. J. W.), National Institute of Diabetes, Digestive and Kidney Diseases, and the Surgery Branch, National Cancer Institute (J.A.N.), National Institutes of Health, Bethesda, Maryland 20892 ABSTRACT We report a family with primary hyperparathyroidism in four patients in two generations with apparent autosomal dominant transmission. A fifth member was probably affected. Two cases had definite parathyroid carcinoma (PC), and two had parathyroid adenoma with atypical features that could represent an early stage of cancer. In each of our patients, one parathyroid gland was abnormal. Five other parathyroid glands (in two patients) were normal in histology and size. There was no evidence of neoplasia in other tissues. Constitutional karyotypes were normal in all four patients. We identified three chro-

F

tumor syndromes point to genes important in cell growth regulation (1, 2). There is a limited number of such syndromes, and the abnormal gene remains unknown in most, The genes causing rare familial tumor syndromes, such as retinoblastoma, can have broad implications (3). Familial parathyroid cancer (PC) is extremely rare. Although isolated casesof PC have been reported in familial hyperparathyroidism (HPT) due to parathyroid adenoma (4), parathyroid hyperplasia (5-7), and multiple endocrine neoplasia type 1 (MEN-l) (8), there are only two reports of PC in more than one member of a family (9, 10). In both kindreds, PC was diagnosed in siblings. We report a family with HPT in two generations, with apparent autosomal dominant transmission. Two caseshad definite PC, and two had parathyroid adenoma with atypical features, but did not meet all of the criteria for PC. AMILIAL

Materials Standard

laboratory

and Methods

analyses

mosomal abnormalities (a reciprocal translocation between chromosomes 3 and 4, trisomy 7, and a pericentric inversion in chromosome 9) in cultured PC tissue from one patient. These chromosomal changes are of unclear significance. Analyses on tumor DNA from one case of PC and one of atypical adenoma showed no evidence of ras gene mutations, PTH gene rearrangement, or allelic loss from chromosome llq13 (locus of the gene for multiple endocrine neoplasia type 1). This family shows susceptibility to cancer without antecedent hyperplasia in all parathyroids. It could help identify a novel tumor susceptibility gene. (J Clin Endocrinol Metab 75: 362-366, 1992)

Chromosomal

analysis

Chromosomal analysis was performed on peripheral blood and skin fibroblasts with standard methods, including Giemsa-trypsin banding (11). Chromosomal analysis was also performed on cultured cells from surgical samples of parathyroid carcinoma from cases II-3 and 111-3. Tumors obtained at surgery were digested with Dispase (50 U/mL) for 90 min, mechanically dispersed, and cultured in 1:l Ham’s F-12:Dulbecco’s Modified Eagle’s Medium with 20% fetal calf serum at 37 C in an atmosphere of 95% humidified air and 5% C02. Established cultures, second to fourth passages, were treated with colcemid (0.05 rg/mL) for 6-12 h, and metaphase spreads were analyzed as described above.

Molecular

studies of tumor tissue

Southern blot analysis. DNA was extracted from fresh surgical specimens, peripheral blood leukocytes, cultured skin fibroblasts, and cultured tumor cells. DNA was digested, and blots were prepared as previously described (12). The blots were probed with a PTH probe located at 11~15.4 (pPTHm122, kindly supplied by Dr. H. Kronenberg, Massachusetts General Hospital) and with int2 and PYGM, both located at llq13

(12). Polymeruse chain reaction (PCRJ and allele-specific hybridizations (ASO). Genomic DNA fragments (from tumor), including codons 12, 13, and 61 of Ha-ras, N-ras, and codons 12 and 13 of Ki-rus, were amplified by PCR and screened for known activating point mutations by ASO, as previously described (12).

The four members with HPT were evaluated as in-patients at the NIH from 1986-1991, during which time each had at least one parathyroid operation. Other family members were tested during 1988-1989; serum and plasma were frozen and shipped to the NIH for analysis. Serum calcium, albumin, and creatinine were measured by standard automated techniques. PTH (intact and midmolecule assays) in plasma and gas&in and PRL in serum were measured by RIA in all available family members.

Case reports

Received July 23, 1991. Address all correspondence A. Streeten, 3450 Ellicott Maryland 21043.

As shown in the pedigree (Fig. l), there were four family members with definite and one with suspected HPT. A summary of the casehistories is shown in Table 1. CasesII3 and III-2 had definite PC. This diagnosis was established

and requests for reprints to: Dr. Elizabeth Center Drive, Suite 205, Ellicott City,

Results

362

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KINDRED

WITH

PARATHYROID

CARCINOMA

363

(4 X 2 mm and 6 mm). Length dimensions were all normal for the three glands from patient III-l; width and thickness dimensions were not significantly above normal (glands measured 8 X 5 X 3, 5 X 5 X 5, and 4 X 2 X 2 mm). Gland weights were not determined. The adipose fraction appeared to be normal in these five glands (30-50s). Patients II-3 and III-2 had their initial operations performed elsewhere. Each had one clearly abnormal parathyroid gland; information on their other glands is lacking. FIG. 1. Pedigree showing members affected by hyperparathyroidism due to parathyroid carcinoma and atypical adenoma. Current age or age at death is shown below symbols. All members shown were screened for HPT, except patient IV-13 (0 and W, PC or atypical adenoma; @, suspected PC or adenoma). The arrow indicates the member first diagnosed.

by aggressive local tumor recurrence and typical histological features. In patients II-3 and 111-2,multiple operations, using intraoperative ultrasound (13) and monitoring of urinary CAMP (14) to ensurewide excisionsof local metastases,were able to restore normocalcemia for substantial intervals. Cases III-1 and III-3 had parathyroid adenoma with atypical features; each has had one operation. Patient III-2 had hyperprolactinemia (PRL, 50-88 pg/L; normal, ~20); a cyst at the baseof the pituitary was seen on magnetic resonance imaging, but no pituitary tumor was noted. Gastrin levels were normal in patient 111-2.Patients 11-3,III-l, and III-3 had normal levels of gastrin, PRL, and hCGa. All other family members screenedhad normal calcium, PTH, gas&in, and PRL levels. Dental radiographs were available only in patient II-3 and showed no evidence of jaw tumors.

Chromosomal

analysis

In case R-3, chromosomal analysis from cultured tumor tissue and surrounding connective tissue from his fourth operation (September 1987), in culture for 7 weeks, revealed a clone (8% of 50 cells examined) with a reciprocal translocation between chromosomes3 and 4: 46,XY,t(3;4) (p13;21). In the same chromosomal preparation, there was another clone (10% of cells) with trisomy 7: 47,XY +7. Analysis of cultured tumor tissue (40 metaphases)from his fifth operation (February 1988), in culture for 5 weeks, revealed a different clone of cells with 46,XY,inv(9) (p24q12) in 12.5% of cells. Analysis of 50 metaphasesfrom the same patient’s cultured skin fibroblasts was normal, 46,XY. In case111-3,the karyotypes of tumor and adjacent connective tissue, in culture for 8 weeks, and from cultured skin fibroblasts were normal, 46,XY. Peripheral blood karyotypes of patients III-1 and III-2 were also normal. Cultured tumor tissue was not available for chromosomal analysis in patients III-I and III2. Tumor DNA analysis

Parathyroid

histology

A summary of histological features in abnormal parathyroid tissueis shown in Table 2. Parathyroid tumors from two patients, II-3 and 111-2,had clear-cut malignant features, including local recurrencesrequiring multiple surgical resections. Tumors from these two patients displayed abundant mitoses, trabecular pattern of growth, and thick fibrous bands. The tumor from patient II-3 also showed vascular invasion and areasof necrosiswith cystic degeneration. The small areas of cystic degeneration were not thought to be consistent with cystic parathyroid adenomatosis (15). The diagnosismade on both patients by the outside hospital after their first two surgeries was atypical adenoma; the NIH diagnosisof those slideswas PC. Parathyroid pathology was consistent with atypical adenoma in patients III-1 and 111-3. The diagnosis of carcinoma in these two patients was precluded by absenceof the following features: local or distant spread, abundant mitoses, vascular invasion, and capsular invasion. In patients III-1 and 111-3,additional parathyroid glands were removed and felt to be normal on inspection at surgery and normal in histology. These glands were normocellular and had no evidence of cysts. The normal parathyroid gland measuresup to 8 mm in length, 5 mm in width, and 2 mm in thickness, and weighs up to 75 mg (16). All dimensions available for the two glands from patient III-3 were normal

On Southern blot analysis, leukocyte DNA from both patients II-3 and III-3 displayed heterozygosity with probes pPTHm122, int 2, and PYGM and were, thus, informative to explore for loss of heterozygosity along chromosome 11 in tumor tissue.There was no lossof heterozygosity in either the fresh tumor specimens or cultured tissue (data not shown). In addition, there was no evidence for the PTH gene rearrangement previously demonstrated in sporadic benign parathyroid tumors (data not shown) (17). Using PCR and AS0 (see Materials and Methods), tumor DNA from patients II-3 and III-3 revealed no evidence of activating point mutations in the Ha-ras, N-ras, or Ki-ras oncogenes(data not shown). Discussion

In this unique kindred, HPT was caused by neoplasia of one parathyroid gland in four patients in two generations.In two patients, the parathyroid tumors were clearly malignant; in the other two, the tumor was an adenoma with atypical features. A fifth patient died with features suggestingsevere primary HPT at autopsy, but parathyroid status was not tested. We feel that the HPT in this family is distinct from previously described syndromes of familial HPT. Jaw tumors, typical of hyperparathyroidism-jaw tumor syndrome (18)

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364

STREETEN

TABLE

ET AL.

JCE & M. 1992 Vol75.No2

1. Summary of clinical course of four patients with HPT and one with suspected HPT

Patient II-3

Monthfyr 36 84

9187

Weakness

3.6

7.5x

3188

3.6

8.3x

7189 5190

Malaise, left neck mass palpable Asymptomatic Weakness

2.2 3.0

2.3x 2.5x

a/91 7191

Asymptomatic Fatigue, bone pain

3.5

3x

53 81

Birth year Multiple pathological fractures

3.5

84

Asymptomatic

3.6

86

NIH referral asymptomatic

52 82 83 86 2189

III-3

56 87 11/88

II-1

PTH (X upper normal)

7186

l/89 III-1

Ca bM)

Birth year Nausea, hone pain, weight loss, headache Anorexia, bone pain, weight loss NIH referral

4186

III-2

Clinical feature

31 62

3.4

2.6x

3.5

1.7x

3.5

3.7x

Surgery Removed 2 PTG (no size given) Removed PT tissue + left thyroid lobe Removed 2 left neck masses, 3 and 2 cm Removed right neck mass, 1.5 cm Removed 2 left neck masses, 2 and 0.5 cm

ICa (Rx Ca + D)

Removed masses, right, mid, and left neck, right thyroid

Normal Ca

No change Ca, L VC paralysis JCa (Rx Ca + D) No change Ca ACa (Rx Ca + D)

Distant bone and lymphatic metastases Removed right neck mass, 3

ACa (Rx Ca + D)

1.5x

Rlgved

3.5

1.8x

Removed right neck mass, 1 cm

JCa, R VC paralysis 1Ca (Rx Ca + D)

Asymptomatic on vitamin D + Ca

2.2

Undetectable

Birth year Asymptomatic Asymptomatic NIH referral, asymptomatic

3.0 3.0

2.1x 3x

Asymptomatic

2.2

Normal

Birth year NIH referral, mild indigestion

3.0

3x

Asymptomatic

on Ca + vit D

right neck mass

Removed left neck mass, 3.2 X 1.5 cm, and 2.5 normal PTG

JCa (Rx Ca + D)

Removed right neck mass, 1.2 X 1 cm, and 2 normal glands

JCa (Rx Ca + D)

Undetectable

Birth year Pathological fracture, right lower leg

JCa, Hypocalcemia; PTG, parathyroid

Removed giant cell tumor tibia, died from sepsis. Autopsy: metastatic renal calcifications, PTG not examined, Ca not measured gland; VC, vocal cord; D, vitamin D analog; Rx, treatment.

were not evident clinically nor seen in the available radiographs. Multiple parathyroid cysts, seen in familial cystic parathyroid adenomatosis (15) were not observed in affected or unaffected parathyroid glands. Jackson et al. (18) have suggested that these two syndromes are, in fact, a single

entity that includes at least one kindred with PC. No other tumors were identified to suggest that our family is within the spectrum of MEN-l or MEN-2. One affected member had hyperprolactinemia, but this was attributed to a small cyst in the pituitary stalk; no pituitary tumor was identified. Furthermore, the lack of allelic loss of 1 lq13 in two parathyroid tumors is additional evidence against a diagnosis of MEN-l (12).

The mean age at diagnosis of HPT in our two patients with PC was 38 yr, slightly younger than the mean of 44 (19) to 48 (20) yr in sporadic PC, but similar to the mean age of 26 (9) to 34 (10) yr in the few previously reported cases of familial PC. Our cases, thus, support the previous suggestion that familial cases of PC present earlier than sporadic cases (20). The clinical presentation of PC in sporadic and familial cases is similar, typically with extreme hypercalcemia, a palpable neck mass, nephrolithiasis, and skeletal involvement, as in our two patients (20). The a-subunit of hCG, elevated in some cases of PC (21), was normal in our two cases. The diagnosis of PC is not always straightforward. In some

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KINDRED TABLE

2. Microscopic

features

Trabecular

Patient

Mitoses

growth

A. Microscopic III-3 II-3 III-” III-1

features + + + +

favoring 0 +++ +++ +

Encapsulation

B. Other III-3 II-3 III-2 111-l

microscopic

features + + 0 +

of abnormal Thick bands parathyroid + + + + Pleomorphism/ cellular atypia

+ + + +

WITH

parathyroid VWXlar

invasion

PARATHYROID

glands Tissue/ capsule invasion

carcinoma 0 + 0 0

0 + 0 0

Rim of normal parathyroid

+ 0 0 0

cases, a definitive diagnosis of PC is not made at the initial surgery, but becomes clear only after local recurrence (2225). This was the situation in both of our cases with subsequent unequivocal PC (II-3 and 111-2). There is considerable controversy about the criteria necessary for diagnosis of PC (19, 22-24, 26, 27). The diagnosis is clear when metastases are present, as in our cases II-3 and 111-2, but in their absence, one must rely on histological criteria (23, 28). The classical histological features of PC are mitoses, trabecular pattern of growth, fibrous bands, capsular invasion, and vascular invasion (28). In patients with PC, no single histological criterion, except metastases, is pathognomonic, because each can be seen alone in adenoma (24). Some authors argue that PC cannot be diagnosed in the absence of metastases (29). A subset of parathyroid adenomas displaying some atypical features, as in our cases III-1 and 111-3, may actually represent low grade malignancies or a premalignant state (24). Familial forms of cancer in most tissues are preceded by a diffuse hyperplastic or multifocal nodular stage (30). This is also true for familial forms of cancer in most endocrine tissues (2). In our family, there was no evidence of a hyperplastic parathyroid state preceding PC. Among the four patients evaluated in our report, five unaffected glands from two patients were normal on histology and normal in size. There are only two other kindreds reported with PC in two members, in both cases siblings (9, 10). In one report, each patient had PC in one parathyroid gland and an adenoma in another gland (9). In the second, two siblings had PC of one gland; other glands inspected were normal (10). In the family described here, the finding of PC without an earlier phase of diffuse hyperplasia suggests an unusual mechanism of germ line predisposition to cancer. In certain familial endocrine tumor syndromes, some neoplasms can be diagnosed at a premalignant stage by biochemical screening studies, as with calcitonin testing for C-cell neoplasia in MEN-2. However, this may not be the case in our family, so we advocate total parathyroidectomy for affected patients in this family. We have initiated a search for the genetic etiology of the HPT in our family by using both cytogenetic and molecular biological techniques. Cytogenetic analysis of tumor tissue

CARCINOMA

365

can be valuable in identifying genes important in carcinogenesis, particularly when the chromosomal location of the disease gene is unknown (31). Although a long term culture of PC has been reported (32), we know of no reports of cytogenetic analysis of PC cultures. In patient 11-3, tumor cells were cultured from his fourth and fifth operations, and several abnormalities were noted. Reciprocal translocations between chromosomes have been noted in other solid tumors, including Ewing sarcoma, renal cell carcinoma, malignant melanoma, ovarian cancer, and small cell lung cancer (31). Trisomy 7 has been noted in several solid tumors, including bladder cancer (33), colon cancer (34), and melanoma (35), so it does not seem to be a tumor-specific abnormality, but may have a broad role in tumor evolution. These types of chromosomal abnormalities seem to be nonrandom events (31) and may give insight into the location of genes important in tumor evolution. We cannot draw conclusions about the importance of our cytogenetic findings in the pathogenesis of PC in this family, since we have observed chromosomal abnormalities in cultured tumor specimens from only one patient. We have not looked for similar cytogenetic abnormalities in intact tumor tissue. In addition, we found different rearrangements in the two PC specimens studied from this one patient. Further cytogenetic studies on PC would help to determine the significance of our cytogenetic findings. By Southern blot analysis of tumor tissue, we found no evidence for alielic loss or other rearrangement in the PTH gene(s) at llq13. Clonal rearrangement of the PTH gene has been noted in 3 of 86 PT adenomas (17, 36). Allelic loss from the long arm of chromosome 11 has been found in one fourth of sporadic adenoma and over half of MEN-l parathyroids (36). In summary, we have described a unique family with probable autosomal dominant transmission of susceptibility to PC, with normal histology, no adenoma in other parathyroid glands, and no neoplasia in tissues outside the parathyroids. The disease seems to be distinct from other syndromes of familial hyperparathyroidism and, thus, might help to identify a new gene important in tumor progression. We have identified three cytogenetic anomalies of unclear significance in tumor specimens from the patient with the most aggressive tumor.

References 1. Li Fl’. 1988 Cancer families: human models of susceptibility to neoulasia-The Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res. 48:5381-6. 2. Marx SJ. 1989 Familial multiple endocrine neoplasia type 1. Mutation of a tumor suppression gene. TEM. NcwDec:76682. 3. Benedict WF, Xu HJ, Hu Sx, Takahashi R. 1990 Role of the retinoblastoma gene in the initiation and progression of human cancer. J Clin Invest. 85:988-93. 4. Dinnen JS, Greenwood RH, Jones JH, Walker DA, Williams ED. 1977 Parathyroid carcinoma in familial hyperparathyroidism. J Clin Pathol. 30:966-75. 5. Cope 0. 1960 Hyperparathyroidism: diagnosis and management. Am J Surg. 99:394. 6. Golden A, Canary JL, Kerwin DM. 1965 Concurrence of hyperplasia and neoplasia of the parathyroid glands. Am J Med. 38:562.

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366

STREETEN

7. Kramer WH. 1970 Association of parathyroid hyperplasia with neoplasia. Am J Clin Pathol. 53275. . .- 8. Mallette LE. Bilezikian IP. Ketcham AS, Aubach GD. 1974 Parathyroid carcinoma in familial hyperpa&thyroidism. Am J Med. 57:642-g. 9. Frayha RA, Nassar VH, Dagher F, Salti IS. 1972 Familial parathyroid carcinoma. Lab Med J. 25:299-309. 10. Leborgne J, Le Neel JC, Buzelin F, Malvy P. 1975 Cancer familial des parathyroides. Interet de l’angiographie dans le diagnostic des recidives loco-regionales. J Chir (Paris). 109:315-26. 11. Verma RS, Babu A. 1989 Human chromosomes. Manual of basic techniques. New York: Pergamon Press. 12. Friedman E, Sakaguchi K, Bale AE, et al. 1989 Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. N Engl J Med. 321:213-g. 13. Norton JA, Shawker TH, Jones BL, et al. 1986 Intraoperative ultrasound and reoperative parathyroid surgery: an initial evaluation. World J Surg. 10:631-9. 14. Norton JA, Brennan MF, Saxe AW, et al. 1984 Intraoperative urinary cyclic adenosine monophosphate as a guide to successful reoperative parathyroidectomy. Ann Surg. 200:389-94. 15. Mallette LE, Malini S, Rappaport MP, Kirkland JL. 1987 Familial cystic parathyroid adenomatosis. Ann Intern Med. 107~54-60. 16. Bloom, Fawcett. 1960 Textbook of histology, 9th ed. Philadelphia: Saunders. 17. Arnold A, Staunton CE, Kim HG, Gaz RD, Kronenberg HM. 1988 Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. N Engl J Med. 318:658-62. 18. Jackson CE, Norum RA, Boyd SB, et al. 1990 Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome. Surgery. 108:1006-12. 19. Holmes EC, Morton DL, Ketcham AS. 1969 Parathyroid carcinoma: collective review. Ann Surg. 169:631. 20. Shane E, Bilezikian JP. 1982 Parathyroid carcinoma: a review of 62 patients. Endocr Rev. 3:218-26. 21. Stock JL, Weintraub BD, Rosen SW, Aurbach GD, Spiegel AM, Marx SJ. 1982 Human chorionic gonadotropin subunit measurement in primary hyperparathyroidism. J Clin Endocrinol Metab. 54:57.

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22. Trigonis C, Cedermark 8, Willems J, Hamberger B, Granberg P. 1984 Parathyroid carcinoma problems in diagnosis and treatment. Clin Oncol. lO:ll-9. 23. Smith JF, Coombs RRH. 1984 Histological diagnosis of carcinoma of the parathyroid gland. J Clin Pathol. 37:1370-8. 24. Levin KE, Galante M, Clark OH. 1987 Parathyroid carcinoma versus parathyroid adenoma in patients with profound hypercalcemia. Surgery. 101:649-60. 25. Bichel P, Thomsen OF, Askjaer SAA, Nielsen HE. 1980 Light and electron microscopic investigation of parathyroid carcinoma during dedifferenciation. Virch Arch 386:363-70. 26. McKeown PP, McGarity WC, Sewell CW. 1984 Carcinoma of the parathyroid gland: is it overdiagnosed? Am J Surg. 147:292-8. 27. Anderson BJ, Samaan NA, Vassilopoulou-Sellin R, Ordonez NG, Hickey RC. 1983 Parathyroid carcinoma: features and difficulties in diagnosis and management. Surgery. 94:906-15. 28. Shantz A, Castleman B. 1973 Parathyroid carcinoma. A study of 70 cases. Cancer. 31:600-5. 29. Pyrah LN, Hodgkinson A, Anderson CK. 1966 Primary hyperparathyroidism. Br J Surg. 53:245. 30. Hanahan 0. 1988 Dissectiing multistep tumorigenesis in transgenic mice. Annu Rev Genet. 27:479-519. 31. Heim S, Mitelman F. 1987 Solid tumors. In: Cancer cytogenetics, chapt 11. New York: Liss. 32. Patillo RA, Ruchert ACF, Wilson SD, Hussa RO, Gray RW, Lemann J. 1981 A human parathyroid carcinoma that produces parathyroid hormone: long term maintenance in tissue culture. J Clin Endocrinol Metab. 53:641-4. 33. Gibas Z, Prout GR, Pontes JE, Connoly JG, Sandberp; AA. 1986 A possible specific chromosome change in -transitional cell carcinoma of the bladder. Cancer Genet Cvtoaenet. 19:229-38. 34. Becher R, Gibas Z, Sandberg ‘AK 1983 Involvement of chromosomes 7 and 12 in large bowel cancer. Trisomy 7 and 12q. Cancer Genet Cytogenet. 9:329-32. 35. Balaban G, Herlyn M, Guerry IV D, et al. 1984 Cytogenetics of human malignant melanoma and uremalimant lesions. Cancer Genet CytogenGt. 11:429-39. A ” 36. Friedman E, Bale AE, Marx SJ, et al. 1990 Genetic abnormalities in sporadic parathyroid adenomas. J Clin Endocrinol Metab. 71:293”

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