Takao Obara

Diffuse sclerosing variant of papillary carcinoma of the thyroid. Clinical importance, surgical treatment, and follow-up study

A diffuse sclerosing variant is not very rare among papillary carcinomas of the thyroid when the patients are female and younger than 30 years of age. the variant is characterized by diffuse involvement of one or both thyroid lobes, with dense sclerosis, patchy lymphocytic infiltration, and abundant psammoma bodies. Controversy still exists concerning its prognosis. We reviewed our experience with 14 patients treated between 1958 and 1988. All patients were young females, their age being from 10 to 28 years with a mean of 19.6. Hashimotos thyroiditis had been suspected in nine patients before they came to our clinic. Nowadays the diagnosis of this cancer is possible when we have this entity in mind and detect abundant psammoma bodies either by ultrasonography or by soft‐tissue roentgenography of the neck. Total thyroidectomy with modified neck dissection was carried out in eight patients, subtotal thyroidectomy with neck dissection in five, and lobectomy with neck dissection in one. All of them are alive and well without distant metastasis at a mean follow‐up of 16 years. Because most of the patients with this variant of papillary carcinoma are young women and the prognosis is favorable, a complete resection without causing later recurrence, but also cosmetic and complication‐free surgery, should be considered.

Rb Regulates DNA Damage Response and Cellular Senescence through E2F-Dependent Suppression of N-Ras Isoprenylation

Oncogene-induced cellular senescence is well documented, but little is known about how infinite cell proliferation induced by loss of tumor suppressor genes is antagonized by cellular functions. Rb heterozygous mice generate Rb-deficient C cell adenomas that progress to adenocarcinomas following biallelic loss of N-ras. Here, we demonstrate that pRb inactivation induces aberrant expression of farnesyl diphosphate synthase, many prenyltransferases, and their upstream regulators sterol regulatory element-binding proteins (SREBPs) in an E2F-dependent manner, leading to enhanced isoprenylation and activation of N-Ras. Consequently, elevated N-Ras activity induces DNA damage response and p130-dependent cellular senescence in Rb-deficient cells. Furthermore, Rb heterozygous mice additionally lacking any of Ink4a, Arf, or Suv39h1 generated C cell adenocarcinomas, suggesting that cellular senescence antagonizes Rb-deficient carcinogenesis.

A Large Germline Deletion of the MEN1 Gene in a Family with Multiple Endocrine Neoplasia Type 1

Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome inherited as an autosomal dominant trait. Various heterozygous germline mutations of the responsible gene, MEN1, have been identified within its exons in many, but not all, affected individuals. We here demonstrate, by DNA polymorphism analysis and gene dosage analysis with polymerase chain reaction (PCR), a large heterozygous germline MEN1 deletion in a kindred with MEN1, in whom no mutation could be detected in the PCR‐amplified exons. The deletion spanned an at least 7 kb region containing the entire MEN1 gene. These findings indicate that a large germline deletion of the MEN1 gene, which escapes detection in PCR‐based sequence analysis, should be considered as a potential cause of MEN1.

How to recognize and treat parathyroid carcinoma.

Parathyroid carcinoma is a rare tumor and its clinical course is variable. Differentiation of patients with parathyroid carcinoma from those with parathyroid adenoma is often difficult both preoperatively and at operation. For good results, the surgeon must recognize this disorder and perform an en bloc resection at the initial surgery. A neck dissection is necessary only when there is evidence of regional node metastases. After surgery, periodic follow-up of the serum calcium and iPTH levels is essential. When hypercalcemia recurs or the serum iPTH increases, localization studies with the use of thallium-201 scanning help detect local recurrence and regional lymph node metastases, but unfortunately, this method often fails to localize pulmonary metastases. Chest radiographs and CT scanning are useful for delineating pulmonary metastases. A wide excision of locally recurrent tumor, an en bloc radical neck dissection and mediastinum dissection for lymphatic metastases, and an aggressive surgical resection of lung metastases are recommended. Although these operations are rarely curative, they usually offer definite palliation of the marked hypercalcemia, often for a considerable period. Drugs to lower the serum calcium level and systemic chemotherapy are currently of only limited benefit, and radiation therapy is generally ineffective.

Functioning parathyroid carcinoma: Clinicopathologic features and rational treatment

Parathyroid carcinoma is a rare, reported to be less than 1% of patients with primary hyperparathyroidism. Recently, cell cycle regulators such as the retinoblastoma gene and p53 have been implicated in the pathogenesis of parathyroid carcinoma. Yet definite diagnosis remains difficult not only clinically but also pathologically. However, the clinical presentation, biochemical and hormonal findings, and appearance at the operation may possibly raise suspicion regarding the diagnosis. A radical en bloc resection at the primary operation is most important. Even after a successful initial operation parathyroid carcinoma carries an increased risk of recurrence. There is wide diversity in the interval between the initial operation and the manifestation of metastasis. Histopathology and DNA ploidy are valuable predictors of the clinical outcome. Because the severe hypercalcemia it engenders has catastrophic consequences, proper management of the recurrent hypercalcemia is also mandatory. The lung is the most common site of distant metastasis. Selected patients with pulmonary metastasis of parathyroid carcinoma can obtain significant benefit from aggressive surgical resection even when they have multiple or recurrent lesions. When hypercalcemia is refractory to surgical resection, medical treatment with bisphosphonate has a beneficial effect.

Survival of Patients with Metastatic Malignant Pheochromocytoma and Efficacy of Combined Cyclophosphamide, Vincristine, and Dacarbazine Chemotherapy

CONTEXT About 10% of pheochromocytomas are malignant. Exact survival has not been reported, nor has an analysis of the efficacy of chemotherapy on survival time. OBJECTIVE The aim of this study was to analyze the survival curves and survival times of patients with malignant pheochromocytoma and to determine the efficacy of chemotherapy on prolongation of life. DESIGN An inception cohort and Kaplan-Meier survival analysis was conducted. PATIENTS AND OUTCOME MEASURES Thirty-two patients with metastasized malignant pheochromocytoma were analyzed for survival. Twenty-five patients had undergone excision of their primary tumors. Survival curves were compared among the 16 patients in this group treated with combined chemotherapy using cyclophosphamide, vincristine and dacarbazine (CVD) and the nine patients not treated with chemotherapy. RESULTS The survival curve of the 32 patients declined continuously and linearly to at least 20 yr after the diagnosis of pheochromocytoma. The 50% survival rate was estimated to be 14.7 yr. In the 25 patients whose primary tumor was excised, patients who already had metastases at the time of pheochromocytoma diagnosis had better survival than those whose metastases were found later. The survival rate after diagnosis of metastasis was worse in the CVD group than in controls. When the effects of CVD were examined after stratifying several factors, female gender and adrenal origin of tumor were found to be negative prognostic factors for CVD chemotherapy. CONCLUSION The present study revealed a long survival time. CVD chemotherapy was not shown to extend survival, especially for women and patients with adrenal gland-derived primary tumors.

Flow cytometric dna analysis of parathyroid tumors with special reference to its diagnostic and prognostic value in parathyroid carcinoma

The nuclear DNA content of paraffin‐embedded parathyroid tumors from 49 patients with proven primary hyperparathyroidism was determined by flow cytometric analysis. The lesions included 14 primary and 11 locally recurrent or metastatic lesions from 16 carcinoma patients, 28 single adenomas from 28 patients, and 15 hyperplastic glands from five patients with familial multiple endocrine neoplasia type 1. No abnormal DNA stemline was found in any of the hyperplastic glands. One (3.6%) of the adenomas was aneuploid. There was no difference in ploidy patterns between the primary and recurrent lesions of the carcinomas and five (31%) of the carcinomas expressed aneuploidy. Four of the five patients with aneuploid carcinoma had recurrences including pulmonary metastases. One of them died of this disease 12 years after the initial operation, and all except one of the others are hypercalcemic even after removal of the successive recurrent or metastatic tumors. Of the 11 patients with diploid carcinoma, four had either local recurrence or pulmonary metastasis. Two of them are living with normocalcemia 3 and 6 years, respectively, after removal of the recurrent tumors and the others are alive with mild hypercalcemia. The remaining seven patients with diploid carcinoma, however, have no recurrence 2 to 5 years after the initial operation. Thus aneuploid parathyroid carcinomas are likely to show more malignant behavior than those with a diploid DNA pattern. All of the patients with adenoma and hyperplasia have been normocalcemic after a mean follow‐up‐interval of 37 months. This study indicates that flow cytometric analysis of nuclear DNA content is a valuable adjunct to histologic examination in the diagnosis of parathyroid carcinoma and the prediction of the clinical outcome.

A case of gastric carcinoma associated with excessive granulocytosis. Production of a colony-stimulating factor by the tumor.

A patient with gastric carcinoma exhibited an excessive granulocytosis (58,000/μl) preoperatively, in the absence of overt infection. After resection of the primary tumor, the peripheral leukocyte count decreased promptly to the normal value. In a search for a colony‐stimulating factor (CSF), the tumor was transplanted into nude mice. A marked neutrophilia was observed in the tumor‐bearing mice, suggesting the production of CSF by the tumor. Media conditioned by the primary culture of the tumor cells revealed the presence of CSF activity as well. CSF‐producing carcinomas have been detected in various organs; nevertheless, no cases of gastric carcinoma have hitherto been described. It is of particular interest that in this patient hypercalcemia was not observed, although it often accompanied CSF‐producing tumors reported previously. Therefore, it is suggested that this tumor secreted pure CSF and that the CSF produced by the tumor did not necessarily induce hypercalcemia.

Parathyroid Carcinoma: Etiology, Diagnosis, and Treatment

BackgroundThe goal of the present study was to make our medical practice evidence-based for patients with parathyroid carcinoma.MethodsWe posed six clinical questions relevant to the management of parathyroid cancer. A comprehensive search and critical appraisal of the literature was then carried out.ResultsMost of the literature retrieved was retrospective in design and differed in the definition of carcinoma. The distinction between unequivocal and equivocal carcinoma (or atypical adenoma) was not always made for the study populations. None of the studies indicated reproducibility of outcome measures. Of the histopathological features described in the literature based on the description of Schantz and Castleman, capsular/vascular invasions and trabecular growth pattern were the most specific, and fibrous bands were the most sensitive. None of the patients with “atypical adenoma” developed recurrence, whereas 25% of those with “equivocal carcinoma” did. Mutations in HRPT2, the gene responsible for hereditary hyperparathyroidism with jaw-tumor syndrome, were strongly associated with sporadic parathyroid carcinoma. Severe hypercalcemia and its related clinical symptoms, extremely high levels of parathyroid hormone, osteitis fibrosa cystica, a palpable neck mass, and a relatively large depth–width ratio on ultrasonography, are the important features of parathyroid carcinoma. Disease-specific survival rates reported in the literature were varied, reflecting the differences in the definitions of carcinoma, study populations, and interventions.ConclusionsTo establish valid evidence for patient management in the future, a collaboration of endocrine specialists is essential to conduct well-designed clinical studies for this rare disease.

Surgical strategy for pheochromocytoma: Emphasis on the pledge of flank extraperitoneal approach in selected patients

BACKGROUND Anterior transabdominal exploration has traditionally been advocated as the standard procedure for pheochromocytoma. However, some authors claim that a flank extraperitoneal approach with accurate unilateral localization is justifiable. METHODS Retrospective analysis was performed on 87 patients with pheochromocytoma to determine the appropriateness of extraperitoneal exploration. RESULTS There were 45 men and 42 women with a mean age of 44.7 years (range, 16 to 83 years). Fifteen patients (17.5%) had pheochromocytoma as a part of multiple endocrine neoplasia (MEN) type 2A, and four had familial pheochromocytoma, von Hippel-Lindau disease, or von Recklinghausens disease. All tumors detected by preoperative localization studies were correctly identified and were resected through flank extraperitoneal (45 patients), transabdominal (28), thoracoabdominal (13), and posterior (1) approaches. Tumors were extraadrenal in 14, multiple in 22, bilateral in 12, and unequivocally malignant in 2 patients at the initial operation. Two patients died during the immediate postoperative period, giving an operative mortality of 2.3%. Two patients had persistent disease. During follow-up within a mean period of 5 years (range, 1 month to 13.7 years) 8 patients (9.1%) experienced recurrence or metastasis. Other than the patients with MEN 2, recurrence was not attributable to the operative approach. CONCLUSIONS If a preoperative localization study is accurate, an extraperitoneal approach is justifiable for many patients with pheochromocytomas.