日比 八束

We herein report the case of a patient with critical hyperkalemia after unilateral adrenalectomy (ADX) for aldosterone-producing adenomas, which were coexisting with primary hyperparathyroidism. A right adrenal tumor oversecreting mineral corticoid was identified in a 62-year-old female whose kidney function had been impaired due to primary hyperaldosteronism and hyperparathyroidism. The ADX improved her hypertension with normalization of the plasma aldosterone concentration, but without adequately increasing her plasma renin activity. Her eGFR further decreased postoperatively, hyperkalemia appeared and the serum potassium level rose to 6.3 mEq/L at 3 months after ADX. Then, treatment with calcium polystyrene sulfonate jelly was started. Eight months after ADX, a left lower parathyroidectomy was performed, and the serum calcium and intact parathyroid hormone levels decreased to the normal range. The hyperkalemia was difficult to control within 20 months postoperatively without treatment with calcium polystyrene sulfonate jelly or hydrocortisone. This suggests that unmasking the renal impairment and relative hypoaldosteronism after ADX might induce critical hyperkalemia.

We report a rare case with pheochromocytoma as the first manifestation of multiple endocrine neoplasia type 2A with RET mutation S891A. Bilateral pheochromocytomas were identified in a 54-year-old woman. Screening for RET revealed a rare S891A mutation located in the intracellular tyrosine kinase domain. This mutation was previously recognized as one of the mutations only in cases manifesting solely medullary thyroid carcinomas (MTCs). Since calcitonin stimulation test indicated positive result, total thyroidectomy was performed 1 year after the bilateral adrenalectomy, and C-cell hyperplasia was diagnosed by histopathological examination. Our report suggests that cases with S891A mutation, akin to those with other RET mutations, require screening for pheochromocytoma. In addition, it is indicated that calcitonin stimulation test should be performed even in the unaffected elder cases with S891A mutation although the mutation is classified as lowest risk group on MTC in guidelines.

Accumulating evidences suggest RET gene's involvement in development of the kidney in mice and humans. Although it is well known that RET mutation causes multiple endocrine neoplasia type 2A (MEN2A), thus far only 3 individuals have been reported to have MEN2A and renal agenesis/dysgenesis. We report a MEN2A family with RET mutation in which two asymptomatic carriers presented with unilateral renal agenesis. A 48-year-old woman underwent total thyroidectomy with regional lymph node dissection in our department for medullary thyroid carcinoma. She had earlier surgical treatment for a left adrenal pheochromocytoma at the age of 45. In the screening for MEN type 2 for her three sons, a CT scan for adrenal pheochromocytoma incidentally found unilateral renal agenesis in two of the sons, one of whom had suffered from Hirschsprung's disease (HSCR). They had contralateral kidneys exhibiting compensatory hypertrophy and normal renal function. Genetic analysis detected C618R RET mutation in the proband and her 3 sons, and no other mutations were found in RET as well as glial cell line-derived neurotrophic factor (GDNF). Our data lend support to the hypothesis that constitutive active RET mutation in MEN type 2 might partially impair RET function and thereby cause loss of function phenotype such as renal agenesis or HSCR. © The Japan Endocrine Society.

永続的副甲状腺機能低下症は，甲状腺全摘術で懸念すべき合併症の一つである。今回甲状腺全摘を要する疾患ごとに，副甲状腺の機能温存状況を検討した。その結果，術後１年の時点でintact PTH値が正常値下限であった症例の頻度は甲状腺癌症例で0.78％，バセドウ病で2.0％，非中毒性甲状腺腫では０％であった。また副甲状腺が将来過形成をきたす可能性のある重症慢性腎臓病やMEN2A型への甲状腺全摘を施行した症例では副甲状腺を全摘し，一部前腕筋肉内へ自家移植したがこれらの症例で永続的副甲状腺機能低下症をきたしたものはなかった。副甲状腺の温存状況は個々の症例や対象疾患により様々ではあるが，まずは発見しやすい上腺を確実に術中に同定することが重要と思われる。

当院では，2005年４月以降，１cm以上の甲状腺乳頭癌に対しては甲状腺全摘術およびD2a郭清を基本術式として原則施行してきた。一方，2010年10月に甲状腺腫瘍診療ガイドラインから甲状腺乳頭癌に対する「診断と治療のアルゴリズム」が作成委員会のコンセンサスに基づいて提示され，当院でのその術式選択について再考するべき時期が来たのではないかと考えている。本稿では2005年４月から2013年12月までに甲状腺全摘術およびD2a郭清を施行したT1bN0M0以上の甲状腺乳頭癌症例249例の手術成績を検証し， 'gray zoneの甲状腺乳頭癌に対する術式' を再検討した。現在は外来にて30mCiの放射性ヨードアブレーションが可能となり，gray zone乳頭癌に対し全摘術が選択する施設もあるいは増加してくると思えるが，その一方でその合併症リスクを十分承知して，これを術中回避する努力を絶やさないことが義務づけられる。

乳頭癌を合併した甲状腺好酸性細胞腺腫を経験したので報告する． 甲状腺の好酸性細胞腫瘍は良性， 悪性の鑑別が術前には困難であり， また好酸性細胞癌は悪性度が高いとの報告も散見される． 一般的には手術が第一選択とされているが， 実際に吸引細胞診で好酸性細胞腫瘍が疑われると， どの段階で手術に踏み切るべきか判断に迷うことが多い． 好酸性細胞腫瘍 28 例を集計し， そのうち吸引細胞診で好酸性細胞腫瘍が疑われた 9 例について検討すると， 腫瘍径は 1.5 cm から 13 cm まで， 中央値は 2.5 cm で， 自験例が最も小さかったが， 概ね 2 cm 前後から手術がなされていた． このように， 腫瘍径が 2 cm 前後で手術が施行されていることは， 手術適応の目安になると考えられた．

胸腺様分化を示す癌（以下，ITET/CASTLE）は，甲状腺癌において稀な組織型で，術前診断が困難なことが多い。しかし，腫瘍の局在や細胞診所見よりITET/CASTLEを術前に鑑別の１つとして考慮することは可能である。今回，術前診断が困難であったITET/CASTLEの１例を経験した。文献的考察を加えて報告する。症例は64歳男性。頸部腫瘤を自覚し，当院へ紹介受診となる。頸部超音波検査にて，甲状腺右葉下極から尾側方向へ進展する4.2×4.6×2.9cmの腫瘤を認めた。穿刺吸引細胞診では，乳頭癌・濾胞性腫瘍とは異なる悪性細胞を認めた。FDG-PET/CTにて同部位に集積を認めたが，他の部位に悪性腫瘍を疑う集積はみられなかった。甲状腺右葉切除・頸部リンパ節郭清術を施行。右内頸静脈・右反回神経・食道筋層への浸潤を認めたため合併切除を行った。病理標本では異型上皮細胞が島状・索状に増生しており，厚い結合組織で分画されていた。CD5免疫組織染色で陽性を呈し，ITET/CASTLEと診断した。

There are no current guidelines for the management of familial pheochromocytoma (FP). We tried to determine the optimal management of patients with FP. Among 191 patients with pheochromocytoma who underwent surgical resection between 1979 and 2010, there were 18 FP (13 different kindreds 11 females/7 males mean age at initial operation: 38.7 years). The 18 FP cases comprised 10 with MEN2A, 2 with MEN2B, 4 with von Hippel-Lindau disease, and 2 with FP only, and all pheochromocytomas were of adrenal origin. The number of probands and family members was 9 and 9 respectively. Mean tumor size was 6.4 cm in diameter. Simultaneous bilateral adrenalectomy was performed in 6 patients, and unilateral adrenalectomy was performed as the initial surgery in 12 patients. A metachronous contralateral adrenalectomy was performed in 3 patients, 90, 236 and 312 months after the primary operation, respectively. None of the patients received partial adrenalectomy. Among another 9 patients with unilateral adrenalectomy, contralateral pheochromocytomas were suspected in 4 cases at the initial operation. However, none of these contralateral lesions developed severe symptoms or tumor enlargement during a median follow-up of 116 months. In the remaining 5 patients, pheochromocytoma did not develop in the contralateral adrenals over a median follow-up of 80.5 months. Bilateral lesions of adrenal pheochromocytoma in familial cases occurred in 78% of cases (14/18) 9 patients (including 4 with contralateral pheochromocytoma) did not require a contralateral adrenalectomy during a median follow-up of 119 months. No patients have suffered from Addisonian crisis. The ipsilateral adrenalectomy and follow-up of contralateral small pheochromocytoma is one of the management options to preserve adrenocortical function in FP patients. © Jaypee Brothers Medical Publishers (P) Ltd.

78歳，男性。15年前に他院で甲状腺癌の手術をされたが，12年前に局所再発し摘出術を施行した。11年前，5年前にも局所再発し，放射線を計85Gy照射したが，その後も腫瘍は増大し，1年前より出血量が多くなったため当院外科へ紹介され，外科より当科へ紹介された。<br>初診時右前頸部に易出血性で悪臭を伴う腫瘤を認めた。腫瘍からの出血が多いため右上甲状腺動脈塞栓術を4回施行し，局所コントロールのためにMohs氏法を施行した。Mohs氏法により腫瘍局所からの出血量は減り，腫瘍も縮小して患者のquality of life（QOL）を改善し得た。

Telomerase (TA) activity is known to be present in malignant tumor cells, but not in most somatic differentiated cells. TA shows relatively high activity in thyroid cancer cells, but reports vary. This fact prompted us to elucidate whether cell component inhibitors of TA in the thyroid follicles can modulate its activity. The activity of TA extracted from Hela cells was inhibited by mixing with the supernatant fraction of human thyroid tissue extract. To examine the effect of iodine, thyroid hormones (-T3 and -T4) and human thyroglobulin (hTg) contained in the thyroid follicles, -T3, -T4 and hTg were added to the TRAP assay system in vitro, using TA from Hela cells. Iodine, -T3 and -T4 did not affect TA activity, but hTg inhibited the TA activity in a dose-dependent manner (IC50 of hTg: ca 0.45M: inhibiting concentration of hTg was from 0.15M to 3.0M). The hTg inhibition was not evident in the RT-PCR system, suggesting no effect of hTg on Taq DNA polymerase activity. The hTg inhibition of TA activity was attenuated by dNTP but not significantly by TS primer. These data suggest that hTg contained in thyroid follicular cells of various thyroid diseases may affect the TA activity measured in biopsied thyroid specimens, and that the reduction of the TA activity by hTg may induce slow progression and growth, and low grade malignancy of thyroid cancer, particularly differentiated carcinoma.

The tissue distribution of Cu/Zn- and Mn-superoxide dismutases (SOD) in adrenal tumors was studied by an immunohistochemical technique, and the concentrations of both SODs were measured by a sensitive sandwich enzyme immunoassay technique. In the normal adrenal gland, both Cu/Zn- and MnSODs were localized predominantly in the reticular zone of the cortex. Cu/Zn-SOD was stained clearly in the inner fascicular zone of the cortex, but not in the medulla, whereas Aln-SOD was stained weakly in the medulla. In different adrenal tumors, the localization of both stained SODs reflected the origin of the tumor cell. Thus, in one section of a pheochromocytoma only Mn-SOD was stained clearly. The concentrations of both SODs in the tissues of medullary tumors were lower than those in the normal adrenal gland and adrenocortical adenomas. The concentration of Cu/ZnSOD in the tumor tissue of Cushing's syndrome adenoma was higher, and that of Aln-SOD was lower than the concentrations in the normal adrenal gland. The ratio of the tissue concentrations of Aln-SOD to Cu/Zn- SOD was lower in adrenal medullary tumors and Cushing's syndrome adenomas than in the normal adrenal gland and primary aldosteronism adenomas, indicating the predominance of Cu/Zn-SOD in the former, and Aln-SOD in the latter. These data suggest that the localization of Cu/Znand Mn-SODs in adrenal tissues reflects the specificity of the adrenal cells that produce the tissue-specific hormones. An investigation of changes in these enzymes in adrenal tumors may also provide useful information on adrenal tumor cell differentiation. (c) 2006 Elsevier Inc. All rights reserved.

Context: Hyperplasia of parathyroid glands in patients with chronic renal failure is classified into diffuse (DH) and nodular (NH) types, and NH is often refractory to routine medical therapy. Objective: Although it is considered that the parenchymal cells initially proliferate diffusely and then some of them are transformed to form nodules consisting of monoclonal cells, the underlying molecular mechanism for such a transformation is not fully understood. In this study we tried to identify the genes that are up-regulated in NH. Design and Setting: The cDNA population prepared from DH was subtracted from that prepared from NH by a PCR-based cDNA subtraction method. The resultant cDNAs were cloned and sequenced. To confirm the up-regulation of the identified genes, a total of 35 parathyroid glands ( 18 DH, 16 NH, and one mixed) obtained from 21 patients were analyzed. Results: One of the nuclear genes identified was the PRKAR1A gene, which encodes type I alpha regulatory subunit (RI alpha) of cAMP-dependent protein kinase (PKA). Immunohistochemical analysis demonstrated that RI alpha was abundantly expressed in the nodular region, whereas the adjacent diffuse region displayed relatively low expression. Northern and Western blot analyses demonstrated up-regulation of RI alpha expression in most NH tested. Determination of PKA activities revealed that free PKA activities measured in the absence of cAMP in the assay were inversely correlated with RI alpha expression, indicating the functional significance of RI alpha up-regulation. Conclusions: These results suggest that the aberrant expression of RI alpha is involved in the diffuse to nodular transformation of hyperplasia of parathyroid glands by impairing cAMP/PKA signal transduction.

A recent western study reports that t(2; 3)(q13; p25) translocation resulting in the expression of the Pax8-PPARgamma fusion gene in patients with thyroid follicular carcinoma (FTC) occurs with high incidence (63%). Furthermore, the products of the fusion gene were shown to suppress the function of PPARgamma in a predominantly negative manner, conferring them with an oncogenic potential. We examined the expression of this fusion gene in FTC in Japanese patients. From 1989 to 2000, six cases with FTC were surgically treated at our institute. In these carcinoma samples, the expression of mRNAs for the Pax8-PPARgamma fusion product was analyzed by nested RT-PCR. Their expression was also studied in other thyroid nodules (12 adenomatous goiters, 12 follicular adenomas, 12 papillary carcinomas and 12 normal thyroid tissues) obtained at surgery during the same period. Pax8-PPARgamma fusion mRNA was not detected in any FTC samples nor in the other samples. Furthermore, none of the 6 FTCs, one follicular adenoma or one normal thyroid analyzed by fluorescence in situ hybridization (FISH) exhibited Pax8-PPARgamma gene fusion. These findings are in contrast to previous reports and indicate that ethnic background may affect the translocation.

Background. An accurate diagnosis of inferior vena cava (TVC) invasion is important in deciding the surgical strategy for a large adrenal tumor. We investigated the diagnostic value of intracaval endovascular ultrasonography (ICEUS) for invasion of the TVC by a large adrenal tumor. Methods. Nine of 163 patients with adrenal and retroperitoneal tumors underwent ICEUS between 1993 and 2002. Intravascular ultrasonography was performed through the right femoral vein with the use of an 8Fr, 20-MHz transducer. The diagnostic criterion for detecting IVC invasion with ICEUS was identification of destruction of a single echogenic layer of the TVC wall or identification of an intracaval tumor mass. The ICEUS finding was confirmed by pathologic examination. Results. The mean diameter of the tumors in 9 patients undergoing ICEUS and resection was 12.6 cm (range, 8.6-16 cm). Pathologic diagnosis varied: adrenocortical carcinoma, 4, malignant pheochromocytoma, 1; leiomyosarcoma, 1; metastatic lung cancer, 1; paraganglioma, 1; and neurilemmoma, 1. Vascular invasion was identified in 2 patients by ICEUS and confirmed by examination of resected specimens. The sensitivity, specificity, and positive predictive values of ICEUS for the diagnosis of the TVC invasion were 100%, 100%, and 100%, respectively. However, these values far computed tomography were 100%, 14%, and 25%, respectively, and for cavography, 100%, 57%, and 40%, respectively. Conclusions. ICEUS provides confirmatory information regarding tumor invasion of the TVC. This modality also can assist in formulating an operative strategy for large adrenal or retroperitoneal tumors.

Background. Parathyroidectomy (PTx) is the most successful treatment for advanced secondary hyperparathyroidism (2HPT) not responsive to medical treatment. However, persistent HPT remains problematic after PTx if some glands remain. The clinical course in patients with persistent 2HPT was evaluated to clarify the risk for re-operation after PTx. Methods. Between March 1981 and December 2001, initial total PTx with forearm autograft were performed in 1156 uraemic patients. Persistent HPT cases were defined as those in which the lowest postoperative intact parathyroid hormone (i-PTH) concentration was &gt;60 pg/ml, and patients were classified into groups A, B and C, with i-PTH concentrations of greater than or equal to500 300-500 and 60-300 pg/ml, respectively. These patients were followed for 7-234 months after PTx. Results. Persistent HPT was identified in 49/1156 patients (4.2%), with nine cases in group A, 10 in group B and 30 in group C. Re-operation was required in 21/49 (42.8%) cases, and in seven of these the last i-PTH concentration was greater than or equal to500 pg/ml. All cases in group A required re-operation. In group C, 11/30 (36.7%) patients required re-operation. The missed glands removed at re-operation were supernumerary in 14 cases, and located in the mediastinum in 13 cases. The frequency of advanced HPT and re-operation was not negligible. Conclusions. To prevent persistent 2HPT, all parathyroid glands must be found and resected during the initial operation. Even if small parathyroid glands remain, there is a risk of progression. Complete PTx is the first treatment choice for advanced 2HPT.

Adrenalectomy is ideally suited to minimally invasive surgery based on the characteristics of adrenal tumours, which are usually small and benign. The aim of this study was to verify that laparoscopic adrenalectomy is minimally invasive and to assess the indication of laparoscopic adrenalectomy for incidentaloma. From October 1995 through August 2002, 133 patients underwent adrenal surgery at the Department of Surgery II, Nagoya University School of Medicine. Of these, 111 underwent laparoscopic adrenalectomy. All laparoscopic adrenalectomies were performed using the transabdominal lateral approach. In 50 of 133 patients, the adrenal tumours were incidentally discovered. There were 27 non-functioning adrenal tumours and six of seven preclinical Cushing's syndrome cases incidentally discovered. Six of 27 non-functioning adrenal tumour patients underwent open adrenalectomy because of large tumour size or malignancy. Based on the present criteria for laparoscopic adrenalectomy, 15 of 133 patients were retrospectively considered to have required open adrenalectomy. The average size of a non-functioning adrenal tumour was 5.8 cm in diameter, which was equal to the average size of a phaeochromocytoma. A simultaneous bilateral laparoscopic adrenalectomy was performed in a patient in poor condition with advanced Cushing's syndrome due to adrenocorticotrophic hormone-independent macronodular adrenocortical hyperplasia (AIMAH). The adrenal glands were successfully removed without fragmentation in this patient, and the postoperative course was uneventful, thanks to the minimally invasive surgery. The laparoscopic technique assures less morbidity and faster recovery, and appears to be equally effective in eradicating functioning and non-functioning adrenal masses. The benefits of the laparoscopic approach to adrenalectomy should not result in a more aggressive attitude toward the excision of clinically silent, benign-appearing adrenal incidentalomas.

Reoperation for secondary hyperparathyroidism (HPT) due to uremia (2HPT) may be required among patients with persistent renal failure if not all parathyroid glands are removed at the initial operation. Between March 198,1:and July 2001, altogether 1110 patients underwent total parathyroidectomy with forearm autograft for advanced 2HPT in our department. In this study, we evaluated the clinical features of patients who required reoperation and classified them into persistent HOT [the lowest intact parathyroid (PTH) level after initial operation remained high. er than 60 pg/ml] and recurrent HPT (the lowest intact PTH level was normalized after surgery but reelevated became high enough to require reoperation). Removal of residual glands was indicated in 30 (2.7%) cases for persistent or recurrent HPT. All remaining glands were detected by preoperative imaging diagnoses. In 44 (4.0%) patients persistent HPT was recognized and in 15 of them (1.4% of all cases) reoperation was required. In 11 cases, the responsible glands were supernumerary ones removed from the mediastinum. In 4 cases, the glands were resected from the neck In 15 cases (1.4%), reoperation was per formed for recurrent HPT when residual glands were left either in the neck or in the thymic tongue. In all but one case, the missed glands were supernumerary. This study reveals that it is often difficult to avoid persistent HPT induced by mediastinal supernumerary glands and recurrent HPT caused by small glands left in the neck Our findings indicate that patients with uremia should be closely followed considering the possibility that persistent or recurrent HPT may occur after parathyroidectomy.

In the surgical treatment of secondary hyperparathyroidism (2HPT) due to uremia, it is considered necessary to remove all parathyroid glands from the neck to prevent persistent and recurrent parathyroid hyperfunction. However, in some cases fewer than four parathyroid glands can be recognized at initial operation; in the present study, we evaluated the long-term prognosis and estimated surgical strategy in such cases. Between March 1981 and January 1999, 822 patients underwent total parathyroidectomy (PTx) with forearm autograft for advanced 2HPT at the Department of Transplant Surgery of Nagoya Second Red Cross Hospital. In 21 cases (2.6%) fewer than four parathyroid glands were macroscopically found at the initial operation. These cases were followed up and their parathyroid function was evaluated by measurement of intact parathyroid hormone (PTH). In 20 of the 21 cases three glands were found, in I patient only two glands. In 5 of these cases the fourth gland was identified first after postoperative histopathologic evaluation. In all these cases the intact PTH level was normalized. In 8 of the remaining 16 cases high PTH levels persisted after the initial operation, including 3 patients who underwent neck reexploration. However, in the other 7 patients PTH levels dropped within normal range immediately after PTx and a fourth gland has never been recognized. One patient was lost to follow-up. Thus, using our operative strategy, 12 of 822 cases (0.85%) did not develop persistent or recurrent HPT even though only three glands were identified at the operation, To avoid postoperative hypoparathyroidism, autotransplantation should be performed when fewer than four parathyroid glands are found at the initial operation.