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Previous Volume 330:757-761 March 17, 1994 Number 11 Next

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ABSTRACT

Background The origin and molecular pathogenesis of parathyroid carcinoma are unknown. This life-threatening cause of primary hyperparathyroidism cannot be reliably distinguished from its benign counterpart on the basis of histopathological features alone. Because the PRAD1, or cyclin D1, gene, a cell-cycle regulator, has been implicated in a subgroup of benign parathyroid tumors, we examined the possibility that another cell-cycle regulator with possible functional links to PRAD1, the retinoblastoma tumor-suppressor gene (RB), might be involved in the molecular pathogenesis of parathyroid carcinoma.

Methods Parathyroid carcinomas from 9 patients and adenomas from 21 were studied for evidence of tumor-specific loss of RB gene DNA (allelic loss) by analysis of four DNA polymorphisms and for evidence of altered expression of RB protein by immunohistochemical staining.

Results All of 11 specimens from 5 patients with parathyroid carcinoma and informative DNA patterns and 1 of 19 specimens from 19 patients with parathyroid adenoma and informative DNA patterns lacked an RB allele. Fourteen of 16 specimens (88 percent) from the nine patients with carcinoma had abnormal expression of RB protein (a complete or predominant absence of nuclear staining for the protein). None of the 19 adenomas, including the tumor with loss of an RB allele, had unequivocally abnormal staining for RB protein.

Conclusions Inactivation of the RB gene is common in parathyroid carcinoma and is likely to be an important contributor to its molecular pathogenesis. The presence of such inactivation may help to distinguish benign from malignant parathyroid disease and may have useful diagnostic, prognostic, and therapeutic implications.

In contrast to many human tumors in which pathogenetic lesions in various oncogenes and tumor-suppressor genes have been described, no oncogenic molecular abnormalities have been observed in parathyroid carcinomas. However, one oncogene has been identified in a subgroup of benign parathyroid adenomas: PRAD1, or cyclin D1, a cell-cycle-regulator gene activated by a chromosome inversion that places it under the influence of the regulatory region of the parathyroid hormone gene^10,11. The recognition of the role of PRAD1 suggests that other cell-cycle regulators may also be important in the pathogenesis of parathyroid tumors. One quite likely candidate is the retinoblastoma tumor-suppressor gene (RB),¹² whose normal growth-restraining activity depends on the cell cycle^13,14,15 and whose protein product may interact with cyclin D1^16,17. Inactivation of the RB gene has been implicated in the pathogenesis of a number of human cancers,^12,18 but its potential role in parathyroid carcinomas is unknown.

Methods

Patients and Tumor Specimens

Paired samples of peripheral blood (or other nontumor specimens) and parathyroid tissue were obtained from patients who underwent surgery for primary hyperparathyroidism. Patients were categorized as having either parathyroid carcinoma (9 patients) or adenoma (21 patients) according to accepted clinicopathological criteria¹⁹. All patients given the diagnosis of carcinoma had evidence of either gross invasion or distant metastasis, except one patient (Patient 1, Table 1) who had a parathyroid tumor that was strongly suspected to be a carcinoma for the following two reasons: the patient presented with a palpable neck mass and severe hyperparathyroidism (nephrocalcinosis with impaired renal function, diffuse osteopenia with bilateral fractures of the femoral neck, symptomatic hypercalcemia, and a serum parathyroid hormone level 42 times normal), a constellation of findings uncommon in benign parathyroid disease^1,2,5; and the tumor had several histopathological features suggestive of carcinoma -- a dense fibrous capsule; a trabecular cellular architecture; numerous mitotic figures, including abnormal forms; and possible capsular invasion^20,21. No patient had had irradiation of the neck or clinical manifestations of multiple endocrine neoplasia. One patient with parathyroid carcinoma (Patient 2, Table 1) had a family history of benign parathyroid disease.

View this table: [in this window] [in a new window]   Table 1. Results of Studies of Loss of RB Alleles and Staining for RB Protein in Patients with Parathyroid Neoplasms.

 
At initial parathyroidectomy, the nine patients with parathyroid carcinoma ranged in age from 20 to 61 years (mean, 37.7); four were men, and five were women. Eight patients had symptoms: three presented in hypercalcemic crisis, five had nephrolithiasis or nephrocalcinosis, and five had bone pain or osteopenia; two had both renal and skeletal disease. All the patients had hypercalcemia, with serum calcium levels ranging from 12.2 to 19.8 mg per deciliter (3.04 to 4.94 mmol per liter) (mean, 14.9 mg per deciliter [3.72 mmol per liter]). Serum levels of parathyroid hormone were elevated in all patients. Follow-up data were available for all patients, with follow-up ranging from 0.5 to 22.9 years (mean, 6.6) after parathyroidectomy. Eight patients had metastases to lymph nodes or lungs, one or more locally invasive recurrences, or both. The interval between the initial parathyroidectomy and the first recurrence of tumor ranged from 8 to 85 months (mean, 36.4). During follow-up, four patients died of direct consequences of their parathyroid cancer 17 to 78 months after initial surgery, two remained hypercalcemic with residual disease, and three remained normocalcemic. Eight patients underwent multiple operations for recurrent cancer, often with transient improvement in their hypercalcemia. No patient was treated with radiation therapy or chemotherapy.

The 21 patients with parathyroid adenoma ranged in age from 33 to 77 years (mean, 55.3); 16 were women, and 5 were men. Six patients had nephrolithiasis, and five had bone pain or diffuse osteopenia; none had both renal and skeletal disease. The serum calcium levels ranged from 10.5 to 14.9 mg per deciliter (2.62 to 3.72 mmol per liter) (mean, 11.7 mg per deciliter [2.92 mmol per liter]), and the parathyroid hormone levels were elevated (20 patients) or inappropriately normal in the setting of hypercalcemia (1 patient). During surgery, a single enlarged parathyroid gland was identified and resected in each patient, and the result of histologic examination was consistent with a diagnosis of adenoma; none of these tumors had any histopathological feature suggesting cancer. Follow-up data were available for all patients, with follow-up ranging from 1 to 66 months (mean, 33.3) after operation. No patient had hypercalcemia at any time during follow-up. Patient 21 (Table 1) presented with mild, asymptomatic hypercalcemia (11.3 mg per deciliter [2.82 mmol per liter]); a parathyroid adenoma without atypical features was resected, and the patient has remained normocalcemic for 66 months.

Genomic DNA was isolated from peripheral leukocytes, frozen tissue, or formalin-fixed, paraffin-embedded tissue as previously described^22,23.

Studies of Allelic Loss

Parathyroid tumors were studied for tumor-specific allelic loss of the RB gene, with the use of four polymorphisms within the gene: a BamHI restriction-fragment-length polymorphism (RFLP) in intron 1,²⁴ an XbaI RFLP in intron 17,²⁵ a locus with a variable number of tandem repeats in intron 17 revealed by RsaI,²⁴ and a simple sequence repeat in intron 20 (RB 1.20)²⁶. The BamHI and RsaI polymorphisms were detected by conventional Southern blotting⁴ with random-primed, ³²P-labeled inserts of p123M1.8 and p68RS2.0 (generously provided by Dr. T. Dryja), respectively²⁴. The XbaI polymorphism was detected by amplification with the polymerase chain reaction (PCR) as previously described²⁵ in a reaction buffer containing 2 mM magnesium chloride; the annealing temperature was 53 °C. The RB 1.20 polymorphism was revealed by PCR amplification as described elsewhere²⁷; genomic DNA from frozen tissue was amplified for 30 to 35 cycles, and DNA derived from archival specimens for 40 cycles. A few archival specimens required an additional 30 to 40 cycles.

Immunohistochemical Staining

Paraffin-embedded sections of parathyroid tumor were prepared and stained with the polyclonal RB-WL-1 antibody according to the avidin-biotin complex method^15,28,29. All the tumors were scored by three investigators who worked independently and were unaware of the patient's clinical history and the outcome of genetic analyses. These investigators agreed completely on the first (and subsequent) reviews of most tumors. Infrequent differences in the initial scoring of some tumors were resolved by additional staining and review (with appropriate controls); these tumors are identified in Table 1. A tumor was considered to be RB-positive if it had a heterogeneous pattern of nuclear staining for RB protein throughout the entire section, and to be RB-negative if more than 99 percent of the tumor cells lacked nuclear staining for RB protein and if any nontumor cells in the section did have such staining (positive control). A tumor was considered to be predominantly RB-negative if it contained large areas (representing most of the tumor) that were RB-negative.

Results

Allelic Loss of the RB Gene in Parathyroid Tumors

Functional inactivation of the RB gene requires alterations in both RB alleles,^12,18 resulting in the absence of active RB protein. Often, the RB gene is inactivated by a small structural lesion (a point mutation or microdeletion) in one allele, together with the "loss" of the normal RB allele by chromosomal deletion, mitotic recombination, or another mechanism³⁰. Hence, analysis of allelic loss can be used to screen tumors for RB inactivation. We examined a series of parathyroid neoplasms for tumor-specific allelic loss of the RB gene at four polymorphic loci. Nontumor tissues from five of six patients with parathyroid carcinoma were heterozygous ("informative") at one or more polymorphic RB loci, allowing us to determine whether one of the RB alleles was lost in the corresponding tumors. All 11 carcinoma specimens from these patients showed tumor-specific loss of one RB allele (Table 1). Representative allelic patterns are shown in Figure 1. The archival specimens of three other patients with parathyroid carcinoma could not be analyzed genetically because of DNA degradation.

View larger version (10K): [in this window] [in a new window]   Figure 1. Allelic Loss of the RB Gene in Parathyroid Carcinoma. Samples of genomic DNA from Patients 4 and 1 were examined at different polymorphic loci in the RB gene. The larger RB allele at each locus is arbitrarily termed A1, and the smaller RB allele A2. The DNA from the carcinoma of Patient 4 shows tumor-specific loss of the XbaI allele (A1) in four separate metastases to the lung (T1 through T4); both RB alleles are present in DNA from control samples from the patient -- leukocytes (C) and an adrenal cyst (AC). The DNA from the carcinoma of Patient 1 (T) shows tumor-specific loss of the RB 1.20 allele (A1); both RB alleles are retained in a hyperplastic parathyroid gland (P) and in nontumor control DNA (C) from the patient.

 
In the case of two patients with metastatic parathyroid carcinoma (Patients 2 and 4), genetic data could be obtained by evaluating both the primary tumor and metastases. In each patient, the same RB allele was lost in the primary tumor and in each metastasis, suggesting that the loss of an RB allele is a genetic event that precedes metastasis in the development of a parathyroid carcinoma. DNA from normal leukocytes and a benign adrenal cyst of Patient 4 contained two distinguishable RB alleles (A1 and A2), revealed with use of the XbaI RFLP (Figure 1). However, each of four separate metastases of the parathyroid carcinoma to the lung lacked the A1 allele. Although DNA from a paraffin-embedded section of this patient's carcinoma could not be amplified with the XbaI oligonucleotide primers, analysis at the RB 1.20 locus indicated that the same RB allele was deleted in the primary tumor and in each metastasis (data not shown).

Almost every patient with parathyroid carcinoma in this study had metastatic or locally invasive disease. However, Patient 1 had no evidence of recurrence six months after en bloc resection of the primary tumor; carcinoma was strongly suspected on the basis of clinical and histopathological features (see the Methods section). This carcinoma (Figure 1) also lacked one RB allele. The finding of the loss of an RB allele in a nonmetastatic parathyroid carcinoma gives further credence to the notion that this genetic event occurs relatively early in the pathogenesis of these tumors.

Of 21 parathyroid adenomas, 19 were informative with respect to one or more RB polymorphic loci. In sharp contrast to the parathyroid carcinomas, only 1 of these 19 adenomas showed allelic loss of the RB gene (Table 1). This tumor (from Patient 21) was associated with a clinicopathological presentation and postoperative course typical of a parathyroid adenoma (see the Methods section) and appeared to retain the function of the other RB allele, as described below and as shown in Table 1.

Immunohistochemical Staining for RB Protein

Having demonstrated frequent clonal deletion of one RB allele in parathyroid carcinoma, we analyzed the undeleted allele to confirm the role of inactivation of the RB gene in parathyroid carcinomatosis. Direct genetic approaches to characterizing the undeleted RB allele can miss regulatory mutations and are cumbersome, since the RB gene spans about 200 kb of DNA³¹. In contrast, methods to assess the expression of RB protein are sensitive and technically more feasible^18,32. In retinoblastomas, the lack of immunoreactive nuclear RB protein, reflecting inactivation of both RB alleles, is a common finding³². Consequently, we used a well-characterized polyclonal antibody to the RB protein in the immunohistochemical staining of paraffin-embedded tumor sections.

The results of our study of 16 specimens obtained from the nine patients with parathyroid carcinoma are summarized in Table 1. Ten specimens were negative for RB protein; a representative carcinoma is shown in Figure 2A. Four carcinomas contained large areas that were RB-negative (the tumors were scored as predominantly RB-negative), and two carcinomas were RB-positive. The finding of abnormal (uniformly or predominantly absent) expression of RB protein in 14 of the 16 carcinomas (88 percent) strongly suggests that the allelic loss seen in parathyroid carcinomas is pathogenetically important and not simply a random or secondary genetic event during the clonal evolution of these tumors. The two RB-positive carcinomas may have had intact RB function; one or more other genes may be more important in the pathogenesis of such tumors. Alternatively, it is possible that the RB protein detected immunologically in these tumors is functionally inactive.

View larger version (82K): [in this window] [in a new window]   Figure 2. Immunohistochemical Staining of RB Protein in Two Representative Parathyroid Tumors (Immunoperoxidase, x313). An RB-negative parathyroid carcinoma from Patient 4 (Panel A) has a uniform lack of staining for RB; in contrast, an RB-positive parathyroid adenoma from Patient 14 (Panel B) has a heterogeneous pattern of nuclear staining for RB (stained nuclei are brown), reflecting cell-cycle-dependent fluctuations in the expression of RB protein15.

 
In contrast to the frequently abnormal expression of RB protein in the parathyroid carcinomas, none of the 19 adenomas available for immunohistochemical staining, including the tumor lacking an RB allele, were unequivocally RB-negative (uniformly or predominantly). Thirteen adenomas were readily scored as RB-positive (Figure 2B), and six were determined to be positive after additional staining and review (Table 1); these six tumors had weak nuclear staining. Such variability in the intensity of nuclear staining for RB protein has been described in other tumors and cell lines known to be RB-positive; it probably reflects differing mitotic rates among tumors, since levels of RB protein are cell-cycle-dependent¹⁵ and may be expected to be minimal in slow-growing adenomas.

Discussion

We have shown that the loss of an RB allele is very common in parathyroid carcinomas and that abnormal expression of RB protein is frequently demonstrable in these tumors. These observations clearly indicate that inactivation of the RB gene is important in the pathogenesis of parathyroid carcinoma, probably occurring through functional disruption of both RB alleles.

In contrast, complete inactivation of the RB gene does not appear to occur in parathyroid adenomas. In other tumors, RB inactivation is almost entirely restricted to malignant neoplasms¹⁸. To our knowledge, loss of the RB gene has been reported in only one ostensibly benign human tumor, a single case of insulinoma³³. Benign tumors of other endocrine glands have also revealed no evidence of such loss^27,34. Therefore, in addition to the putative role of RB inactivation in accelerating the progression of the cell cycle, an action that may resemble that of overexpression of the PRAD1 oncogene in benign parathyroid adenomas,^10,11 RB inactivation also appears to contribute to the manifestations of cancer itself. Such malignant cellular effects due to the absence of functional RB gene product may be direct or may occur because of heightened genomic instability, thereby increasing the likelihood of additional genetic events linked to invasion or metastasis.

Given the difficulty of distinguishing parathyroid carcinoma from parathyroid adenoma on the basis of histopathological features alone^5,6,7,8,9 or by flow cytometry,³⁵ our findings also suggest that inactivation of the RB gene may be a potentially useful molecular marker for cancer of the parathyroid. Studies of the RB gene may ultimately be useful in assessing prognosis and planning follow-up treatment for patients with parathyroid neoplasms. Moreover, analysis of the RB status of parathyroid tumors with histologically equivocal features could be used to identify a subgroup of patients in whom early adjuvant therapy might be considered. In the present study, five of nine patients with parathyroid carcinoma were initially given a diagnosis of benign parathyroid disease on the basis of histopathological analysis of the primary tumors. One of these tumors was available for study; it was found to be lacking an RB allele and to be negative for RB protein. This recognition of the role of RB inactivation in parathyroid cancer could also have therapeutic implications. For example, molecules that are regulated by the RB protein could become targets of pharmacologic therapy for parathyroid carcinoma, or normal RB gene or RB protein could be introduced into tumor cells.

Supported in part by grants (1K08 CA-01752-01A1, 1F32 CA-0938101, 5T32 DK-0702817, DK-11794, CA-55909, and CA-54672) from the National Institutes of Health, a Faculty Research Award (FRA-391) from the American Cancer Society (to Dr. Arnold), and a Texas Advanced Technology Program grant (to Drs. Benedict and Xu).

We are indebted to Dr. T. Dryja and J. Rapaport for providing plasmids used in this study and giving technical advice; to Drs. R. Gaz, D. Liechty, and M. Corkill for their assistance in obtaining specimens; to S. Edgerton for technical assistance with the histologic sectioning; and to Dr. D. Yandell for his technical advice.

Source Information

From the Laboratory of Endocrine Oncology, Department of Medicine and Massachusetts General Hospital Cancer Center (V.L.C., A.A.), and the Department of Pathology, Massachusetts General Hospital and Harvard Medical School (A.T., A.L.V.), Boston; the Center for Biotechnology, Baylor College of Medicine, The Woodlands, Tex. (H.-J.X., S.-X.H., W.F.B.); and the Section of Endocrinology, Denver Veterans Affairs Medical Center and the University of Colorado Health Sciences Center, Denver (M.E.W.).

Address reprint requests to Dr. Arnold at Jackson 1021, Massachusetts General Hospital, Boston, MA 02114.

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