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Between March 1981 and December 2000, we performed 1,053 total parathyroidectomies with forearm autograft for advanced renal hyperparathyroidism (HPT). Based on histopathologic and pathophysiologic investigations, surgical treatment should be considered when parathyroid glands show nodular hyperplasia. Measuring parathyroid volume by ultrasonography was useful to detect nodular glands and to determine surgical indications. The clinical effect of parathyroidectomy on the symptoms and biochemical variables was striking. Skeletal deformity, progressive bone loss, and vessel calcification leading to high mortality risk could not be alleviated by even successful surgery, however. To prevent cardiovascular complications, parathyroidectomy should be performed in the relatively early stage of renal HPT. Total parathyroidectomy with forearm autograft is a suitable procedure for renal HPT, especially in patients who require long-term hemodialysis. For surgeons, it is important to remove all parathyroid glands, including supernumerary glands, at the initial operation and to choose adequate parathyroid tissue for the autograft to prevent persistent and recurrent HPT. Although the risk of graft-dependent recurrent HPT is not negligible, enlarged transplanted parathyroid tissue can be removed easily and noninvasively from the forearm under local anesthesia. There is no risk of hypofunction of the autograft.

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BACKGROUND: In primary hyperparathyroidism, certain genetic abnormalities responsible for parathyroid tumorigenesis are proposed, and it has been reported that the overexpression of PRAD1/cyclin D1 induced by a DNA rearrangement of the parathyroid hormone (PTH) gene is one of the genetic disorders in a number of primary parathyroid adenomas. However, in secondary hyperparathyroidism caused by uremia, the mechanism of monoclonal proliferation in nodular parathyroid hyperplasia is not well understood. To elucidate the mechanism, we examined the expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in primary adenoma and secondary hyperplasia. METHODS: In adenomas (N = 15) and associated glands (N = 7) with normal histology obtained from patients with primary hyperparathyroidism and in diffuse (N = 14), multinodular (N = 58), and single nodular (N = 28) glands from patients who underwent parathyroidectomy for renal hyperparathyroidism, the expression of these cell cycle regulators was evaluated by immunohistochemical technique. A labeling index was used to define the proportion of cells with positive nuclear staining by each antibody. RESULTS: In 6 out of 15 (40%) primary adenomas, PRAD1/cyclin D1 was overexpressed (a labeling index of more than 500), possibly because of the PTH gene rearrangement, but not in secondary hyperplasia, including single nodular glands. Compared with diffuse hyperplasia, nodular hyperplasia showed a significantly higher expression of PRAD1/cyclin D1 (P < 0.05), retinoblastoma gene products (P < 0.05), and Ki67 (P < 0.05). However, no statistically significant correlation between the expression of PRAD1/cyclin D1 and that of Ki67 was observed in both primary adenoma and secondary hyperplasia. CONCLUSIONS: These results suggest that in secondary hyperplasia caused by uremia, at least remarkable overexpression of PRAD1/cyclin D1 induced by PTH gene rearrangement may be not the major genetic abnormality responsible for tumorigenesis. Heterogenous genetic changes seem to contribute to monoclonal proliferation of parathyroid cells induced by the expression of PRAD1/cyclin D1 or by some other mechanism independent of the amplification of the proto-oncogene.

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In secondary hyperparathyroidism (2HPT) fundamentally all parathyroid glands, including supernumerary glands, become hyperplastic, and stimulation of parathyroid glands continues after parathyroidectomy (PTx). Therefore supernumerary glands have special significance during surgery for 2HPT, whether persistent or recurrent HPT. In the present study 570 patients underwent initial total PTx with a forearm autograft. The frequency, type, location, histopathology, and clinical significance of the supernumerary glands were evaluated. At the initial operation 90 supernumerary glands were removed from 82 to 570 patients (14.4%); 12 patients (2.1%) required extirpation of supernumerary glands for persistent/recurrent HPT. Altogether 104 supernumerary glands were identified at operation in 94 of the 570 patients (16.5%). Among these 104 glands, 25 (24.0%) were of the rudimentary, or split, type and 79 (76.0%) of the proper type. Supernumerary glands were most frequently identified in the thymic tongue (53/104, 51.0%); 32 (60.4%) of these 53 glands were identified only microscopically. In 6 of the 570 cases (1.1%), reoperation was required for persistent HPT due to supernumerary glands located in the mediastinum, and 6 patients underwent neck reexploration for recurrence. Histopathologically, 61 of 104 (58.7%) supernumerary glands, including 36 glands recognized only microscopically, showed diffuse hyperplasia, and 43 (41.3%) displayed nodular hyperplasia. Residual small supernumerary glands with diffuse hyperplasia have the potential to be transformed to nodular hyperplasia during long-term hemodialysis. Therefore all parathyroid glands including supernumerary glands should, if possible, be removed at the initial operation. Routine removal of the thymic tongue and careful examination of the regions surrounding the lower poles of the thyroid, especially on the left side, are important steps in the surgical treatment.

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Advanced secondary (renal) hyperparathyroidism induced by chronic renal disturbance is one of the most serious complications for long-term hemodialysis patients. Parathyroidectomy is indicated in patients with severely advanced renal hyperparathyroidism refractory to medical treatment (including calcitriol pulse therapy) and the clinical effect of parathyroidectomy is striking. However, skeletal deformity, vessel calcification, and remarkable reduction of bone content is irreversible, and it is important to perform parathyroidectomy at right time. Based on histopathological and pathophysiological investigations, nodular hyperplasia is monoclonal neoplasia with abnormal parathyroid hormone (PTH) response to extracellular calcium and vitamin D. When parathyroid hyperplasia progresses to nodular hyperplasia, parathyroidectomy should be required. Total parathyroidectomy with forearm autograft is the preferable procedure for renal hyperparathyroidism, especially for patients who need to continue hemodialysis treatment after parathyroidectomy. Removal of all parathyroid glands, including supernumerary glands, at the initial operation, and proper choice of adequate parathyroid tissue for autograft, are important to prevent persistent and recurrent hyperparathyroidism. Preoperative image diagnosis is useful for localization, and routine resection of thymic tissue is necessary to remove supernumerary glands. In our series of 548 patients, graft-dependent recurrent hyperparathyroidism was not negligible and the incidence was about 20% at the 5th year postoperatively. Enlarged autografts of parathyroid tissue could be removed from forearm under local anesthesia with fewer invasions. The function of autografted parathyroid tissue is nearly satisfactory and no re-transplantation of cryopreserved parathyroid tissue was necessary. To avoid adynamic bone disease, relatively high PTH level is required-over-suppression of PTH by excess of vitamin D and calcium salts should be avoided. In our experience, total parathyroidectomy with forearm autograft is very effective and adequate treatment for advanced renal hyperparathyroidism, and parathyroid function can be controlled after parathyroidectomy.

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Although it is well known that chronic renal failure induces parathyroid hyperplasia, the pathogenesis and development of this parathyroid lesion in this disease are poorly understood. Histopathologically, there is progression from diffuse to nodular hyperplasia, and each nodule consists of a single cell type with aggressive proliferative potential. Pathophysiologic and clinical investigations have suggested that neoplastic tumors may emerge from nodular hyperplasia. In this study the clonality of parathyroid tissue in nodular and diffuse hyperplasia in renal hyperparathyroidism was analyzed by a method based on restriction fragment length polymorphism of the X chromosome-linked phosphoglycerokinase gene and on random inactivation of the gene by methylation. DNA of peripheral lymphocytes was screened in 43 women undergoing parathyroidectomy for advanced renal hyperparathyroidism, and 10 of these patients appeared to be heterozygous. Fourteen specimens from these patients were available for clonal analysis. The analysis showed that all four specimens of diffuse hyperplasia were polyclonal, whereas all seven specimens from nodules in nodular hyperplasia and all three samples representing parathyroid tissue removed from forearm because of graft-dependent recurrence were revealed to be monoclonal. It is likely that the clonal origin of each nodule is independent. These results suggest that in renal hyperparathyroidism parathyroid glands initially grow diffusely and polyclonally, and then the cells in the nodules are later transformed monoclonally and proliferate aggressively. From the present study it can be concluded that nodular hyperplasia represents monoclonal parathyroid neoplasia, which might explain why patients with nodular hyperplasia in renal hyperparathyroidism are refractory to medical treatment, requiring parathyroidectomy. To prevent recurrences, nodular hyperplastic tissue should not be left at surgery.

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Between 1973 and 1992, 300 patients underwent parathyroidectomy for secondary hyperparathyroidism due to chronic renal failure in our departments. Using parathyroid glands obtained at operation, histopathological studies were performed, and to estimate pathophysiology DNA analysis of parathyroid cell nuclei and calcium-regulated parathyroid hormone (PTH) secretion in vitro were estimated. PTH mRNA expression was evaluated by in situ hybridization. The typical histopathological findings were asymmetric enlargement, nodularities and increased number of oxyphil cells. Secondary hyperplasia was divided into 2 types: diffuse and nodular type hyperplasia. In the histopathological study nodular hyperplasia indicated more aggressive proliferation. In DNA analysis the relative number of scattered cells in the DNA synthesis phase was significantly greater in nodular than in diffuse hyperplasia. The half of the maximal inhibition of PTH secretion for calcium (the set-point) in the cells from nodular hyperplasia was higher than in the cells obtained from diffuse hyperplasia. However, there was no difference in expression of PTH mRNA in nodular and diffuse hyperplasia. These data suggested that nodular hyperplasia was more progressively hyperplastic, had more aggressive proliferative activities and showed more abnormal regulation of PTH secretion. These results imply that to prevent graft-dependent recurrent hyperparathyroidism after parathyroidectomy, the nodular hyperplastic tissue should not be autografted.

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We report herein the case of a 46-year-old woman on hemodialysis (HD) who developed recurrent renal hyperparathyroidism induced by lung metastasis from parathyroid carcinoma. The patient had been commenced on HD for chronic renal failure about 20 years earlier and had undergone a parathyroidectomy for advanced renal hyperparathyroidism 8 years later. After the initial operation, further explorations of the neck were performed due to recurrence, despite which the hyperparathyroidism persisted and she was finally referred to our department. The appearance of multiple coinlike lesions on a chest X-ray and computed tomography led to the diagnosis of recurrent hyperparathyroidism induced by lung metastasis from parathyroid carcinoma. A pulmonary wedge resection was performed and the metastatic parathyroid nodules were removed. Of the several hypotheses about the etiology of parathyroid carcinoma in HD patients, it is most likely that the parathyroid hyperplasia induced by chronic renal failure develops into carcinoma. Even in renal hyperparathyroidism, we should bear in mind the possibility that metastatic parathyroid carcinoma is a possible source of excess parathyroid hormone secretion at recurrence.

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In spite of recent therapeutic advances, severe overt secondary hyperparathyroidism due to chronic renal failure necessitates parathyroidectomy and recurrent hyperparathyroidism is one of the most significant problems in this patient population. In the present study, the incidence of recurrent hyperparathyroidism was evaluated in relation to the histopathological features. Image cytometric DNA analysis was performed to estimate the proliferative potential of parathyroid tissue. The study comprised 248 patients who underwent parathyroidectomy from 1973 to 1991. The frequency of recurrent hyperparathyroidism after subtotal parathyroidectomy was 4 (21.1%) of 19 patients, the rate of graft-dependent recurrence after removal of residual parathyroid tissue with forearm autograft was 2 (50%) of 4 patients. The frequency of graft-dependent recurrence after total parathyroidectomy with forearm autograft was 16 (7.5%) of 212 patients. The frequency of recurrence was significantly higher (p less than 0.01) when nodular hyperplastic parathyroid tissue was autografted (17 of 68 patients, 25%) than when diffuse-hyperplastic tissue was grafted (1 of 105 patients, less than 1%). All 58 specimens subjected to image cytometric DNA analysis showed a diploid nuclear pattern cytometrically. However, the relative number of scattered cells that displayed cytometric nuclear DNA values outside the main diploid histogram peak was significantly greater (p less than 0.01) in nodular hyperplastic tissue before being autografted and in parathyroid tissue removed at re-operation performed for recurrence than in diffuse hyperplastic tissue. These clinical findings and results of DNA analysis clearly indicated that nodular hyperplastic parathyroid tissue has a higher growth potential, and it is concluded that to prevent graft-dependent recurrence, the nodular type of hyperplastic tissue should not be autografted.

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Reported is a leiomyosarcoma of jejunum that was found in a 61-year-old man who was admitted to our clinic because of an abdominal distension. A CT scan and an ultrasonic examination revealed a giant tumor with a central necrosis in the abdominal cavity. A study of barium that was ingested revealed an elevated lesion without a fistel formation in the jejunum about 25 cm distant from the Treitz ligament. An ultrasonic the guided percutaneous biopsy was done and pathological diagnosis indicated a leiomyosaroma. Surgery was performed on June 16 1989 and the tumor weighing 4,934 g and 30 x 25 x 18 cm in size, was completely resected.

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