悪性褐色細胞腫の診療アルゴリズム

米国内分泌学会による褐色細胞腫診療ガイドラインで示される本症の診断検査を行うべき状況

出典
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1: Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
著者: Jacques W M Lenders, Quan-Yang Duh, Graeme Eisenhofer, Anne-Paule Gimenez-Roqueplo, Stefan K G Grebe, Mohammad Hassan Murad, Mitsuhide Naruse, Karel Pacak, William F Young, Endocrine Society
雑誌名: J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42. doi: 10.1210/jc.2014-1498.
Abstract/Text: OBJECTIVE: The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL).
PARTICIPANTS: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), seven experts in the field, and a methodologist. The authors received no corporate funding or remuneration.
EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews.
CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, European Society of Endocrinology, and Americal Association for Clinical Chemistry reviewed drafts of the guidelines.
CONCLUSIONS: The Task Force recommends that initial biochemical testing for PPGLs should include measurements of plasma free or urinary fractionated metanephrines. Consideration should be given to preanalytical factors leading to false-positive or false-negative results. All positive results require follow-up. Computed tomography is suggested for initial imaging, but magnetic resonance is a better option in patients with metastatic disease or when radiation exposure must be limited. (123)I-metaiodobenzylguanidine scintigraphy is a useful imaging modality for metastatic PPGLs. We recommend consideration of genetic testing in all patients, with testing by accredited laboratories. Patients with paraganglioma should be tested for SDHx mutations, and those with metastatic disease for SDHB mutations. All patients with functional PPGLs should undergo preoperative blockade to prevent perioperative complications. Preparation should include a high-sodium diet and fluid intake to prevent postoperative hypotension. We recommend minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas. Partial adrenalectomy is an option for selected patients. Lifelong follow-up is suggested to detect recurrent or metastatic disease. We suggest personalized management with evaluation and treatment by multidisciplinary teams with appropriate expertise to ensure favorable outcomes.
J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42. doi: 10.1210/jc.2014-...

わが国での褐色細胞腫の診断基準

わが国での悪性褐色細胞腫の診断基準

褐色細胞腫のTMN分類

出典
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1: Malignant pheochromocytoma-paraganglioma: pathogenesis, TNM staging, and current clinical trials.
著者: Alejandro Roman-Gonzalez, Camilo Jimenez
雑誌名: Curr Opin Endocrinol Diabetes Obes. 2017 Jun;24(3):174-183. doi: 10.1097/MED.0000000000000330.
Abstract/Text: PURPOSE OF REVIEW: Pheochromocytomas and paragangliomas (PPGs) are rare neuroendocrine tumors. Over the last 15 years, substantial progress has been made toward understanding the clinical aspects and molecular origins of this disease. Nevertheless, predicting and managing malignancy remains the biggest challenge in clinical practice. The natural history of patients with malignant PPGs has not yet been described, and their prognosis varies. Currently, the diagnosis of malignant PPGs relies on the presence of metastases, by which time the disease is usually advanced. Better understanding of the clinical and molecular characteristics of patients with malignant PPGs has spurred several prospective clinical trials.
RECENT FINDINGS: Several molecular targeted therapies, a novel radiopharmaceutical medication that targets the catecholamine transporter, and immunotherapy are under evaluation for the treatment of patients with malignant PPGs. Furthermore, the identification of clinical predictors of malignancy and survival has led to the first TNM staging classification for PPGs.
SUMMARY: Prospective clinical trials are providing patients with therapeutic options beyond systemic chemotherapy. The knowledge derived from these trials and from the evaluation of the TNM staging in clinical practice will help to clarify how to most effectively treat malignant PPGs.
Curr Opin Endocrinol Diabetes Obes. 2017 Jun;24(3):174-183. doi: 10.10...

症候スコアリングによる褐色細胞腫尤度に基づく患者のトリアージ

参考文献：
Geroula A, Deutschbein T, Langton K, Masjkur J, Pamporaki C, Peitzsch M, Fliedner S, Timmers HJLM, Bornstein SR, Beuschlein F, Stell A, Januszewicz A, Prejbisz A, Fassnacht M, Lenders JWM, Eisenhofer G. Pheochromocytoma and paraganglioma: clinical feature-based disease probability in relation to catecholamine biochemistry and reason for disease suspicion. Eur J Endocrinol. 2019 Oct;181(4):409-420. doi: 10.1530/EJE-19-0159. PMID: 31370000.
 
出典
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1: 著者提供

遺伝性褐色細胞腫の表現型のまとめ

PCC：副腎髄質、PGL：副腎外、APGL：腹部PGL、CPGL：頸部PGL、TAPPGL：胸腹部または骨盤PGL
出典
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1: An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma.
著者: Alexandre Buffet, Nelly Burnichon, Judith Favier, Anne-Paule Gimenez-Roqueplo
雑誌名: Best Pract Res Clin Endocrinol Metab. 2020 Mar;34(2):101416. doi: 10.1016/j.beem.2020.101416. Epub 2020 Mar 10.
Abstract/Text: Paragangliomas and pheochromocytomas (PPGL) are rare neuroendocrine tumours characterized by a strong genetic determinism. Over the past 20 years, evolution of PPGL genetics has revealed that around 40% of PPGL are genetically determined, secondary to a germline mutation in one of more than twenty susceptibility genes reported so far. More than half of the mutations occur in one of the SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), which encode the different subunits and assembly protein of a mitochondrial enzyme, succinate dehydrogenase. These susceptibility genes predispose to early forms (VHL, RET, SDHD, EPAS1, DLST), syndromic (RET, VHL, EPAS1, NF1, FH), multiple (SDHD, TMEM127, MAX, DLST, MDH2, GOT2) or malignant (SDHB, FH, SLC25A11) PPGL. The discovery of a germline mutation in one of these genes changes the patient's follow-up and allows genetic screening of affected families and the presymptomatic follow-up of relatives carrying a mutation.

Copyright © 2020 Elsevier Ltd. All rights reserved.
Best Pract Res Clin Endocrinol Metab. 2020 Mar;34(2):101416. doi: 10.1...

病的変異検出率と変異遺伝子別の有病率

(A)は全対象、(B)は一見、孤発にみえる症例での値を示す。
P/LP: pathogenic/likely pathogenic
B/BL: benign/ likely benign
VUS: variant of unknown significance
出典
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1: Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma.
著者: Masato Yonamine, Koichiro Wasano, Yuichi Aita, Takehito Sugasawa, Katsutoshi Takahashi, Yasushi Kawakami, Hitoshi Shimano, Hiroyuki Nishiyama, Hisato Hara, Mitsuhide Naruse, Takahiro Okamoto, Tadashi Matsuda, Shinji Kosugi, Kazuhiko Horiguchi, Akiyo Tanabe, Atsushi Watanabe, Noriko Kimura, Eijiro Nakamura, Akihiro Sakurai, Kiyoto Shiga, Kazuhiro Takekoshi
雑誌名: Cancers (Basel). 2021 Aug 9;13(16). doi: 10.3390/cancers13164014. Epub 2021 Aug 9.
Abstract/Text: The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype-phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. SDHB was the most frequently mutated gene (57, 15.4%), followed by SDHD (27, 7.3%), and VHL (18, 4.9%). The incidence of metastatic PPGL was high in SDHB carriers (21/57, 36.8%). A few unique recurrent variants (SDHB c.137G>A and SDHB c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population.
Cancers (Basel). 2021 Aug 9;13(16). doi: 10.3390/cancers13164014. Epub...

褐色細胞腫の腹部CT像

図中の矢印は両側副腎の褐色細胞腫を示す。
出典
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1: 著者提供

褐色細胞腫の123I-MIBGシンチグラフィ所見

図中の矢印は核種の異常集積部位を示す。本例では上に示した両側副腎腫瘍に一致した部位（赤の→）に加えて右前頸部に存在する甲状腺髄様癌にも集積（青の→）を認めた。
出典
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1: 著者提供

褐色細胞腫初回診断後の生存率

非進行群と進行群での褐色細胞腫初回診断後（a）、転移性褐色細胞腫初回診断後（b）からの生存率をKaplan-Mayer曲線で示した。非進行群での平均生存期間は各々、15.3±7.6年と8.1±4.4年、進行群では各々、5.9±4.1年と2.6±3.6年といずれも前者が有意に高値だった（各々、p＜0.01とp＝0.02）。
出典
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1: Controlling Tumor Progression with Cyclophosphamide, Vincristine, and Dacarbazine Treatment Improves Survival in Patients with Metastatic and Unresectable Malignant Pheochromocytomas/Paragangliomas.
著者: Shiko Asai, Takuyuki Katabami, Mika Tsuiki, Yasushi Tanaka, Mitsuhide Naruse
雑誌名: Horm Cancer. 2017 Apr;8(2):108-118. doi: 10.1007/s12672-017-0284-7. Epub 2017 Jan 20.
Abstract/Text: Evidence has not been established to support that combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) improves survival in patients with malignant pheochromocytoma and paraganglioma (M-PPGL). To investigate the efficacy of CVD for this disease, we retrospectively analyzed data of 23 patients with metastatic and unresectable M-PPGL (mean age, 41.7 ± 15.4 years) who received at least 2 cycles of this regimen. The follow-up period after initiation of CVD ranged from 0.3 to 13.7 years, with a median of 3.3 years. CVD therapy achieved a complete tumor response (CR) in 1 patient (4%), a partial response (PR) in 5 (22%), stable disease (SD) in 5 (22%), and progressive disease (PD) in 13 (52%), respectively. All of the responders (CR and PR) but 6% of the non-responders (SD and PD) showed substantial biochemical improvement. The progression-free survival period in the responders was significantly longer than in the non-responders (p < 0.01). Although the overall survival and survival after the diagnosis of M-PPGL were longer in the responders than the non-responders, the difference was not statistically significant (p = 0.08). The progression-free and overall survival period were significantly longer in the non-progression group (CR, PR, and SD) than in the progression group (PD) (1.7 ± 3.3 vs. 0.3 ± 0.3 years, p < 0.01, and 4.6 ± 3.6 vs. 2.0 ± 3.7 years, p = 0.01, respectively). It is therefore suggested that CVD chemotherapy could be useful in controlling tumor progression and improving survival in patients with metastatic and progressive M-PPGL.
Horm Cancer. 2017 Apr;8(2):108-118. doi: 10.1007/s12672-017-0284-7. Ep...

CVD療法後の無増悪期間（PFS）

CVD療法後の無増悪期間をSDHB変異の有無で比較した結果。遺伝学的検査未施行の3例は除外した。
CVD療法を行った転移性褐色細胞腫23例を、生存期間をSDHB 遺伝子変異陽性者とそれ以外の例に群分して、後ろ向きに解析した。無増悪期間はSDHB遺伝子変異陽性群で23.67カ月（95％信頼区間12.03-36.5）、それ以外の群で5.17カ月（95％信頼区間0.33-9.7）と前者で有意な期間延長が得られた（p＝0.001）。
出典
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1: SDHB mutation carriers with malignant pheochromocytoma respond better to CVD.
Endocr Relat Cancer. 2017 Aug;24(8):L51-L55. doi: 10.1530/ERC-17-0086. Epub 2017 May 31.

褐色細胞腫の術新予後

出典
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1: European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma.
著者: P F Plouin, L Amar, O M Dekkers, M Fassnacht, A P Gimenez-Roqueplo, J W M Lenders, C Lussey-Lepoutre, O Steichen, Guideline Working Group
雑誌名: Eur J Endocrinol. 2016 May;174(5):G1-G10. doi: 10.1530/EJE-16-0033.
Abstract/Text: Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Standard treatment is surgical resection. Following complete resection of the primary tumour, patients with PPGL are at risk of developing new tumoural events. The present guideline aims to propose standardised clinical care of long-term follow-up in patients operated on for a PPGL. The guideline has been developed by The European Society of Endocrinology and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles. We performed a systematic review of the literature and analysed the European Network for the Study of Adrenal Tumours (ENS@T) database. The risk of new events persisted in the long term and was higher for patients with genetic or syndromic diseases. Follow-up in the published cohorts and in the ENS@T database was neither standardised nor exhaustive, resulting in a risk of follow-up bias and in low statistical power beyond 10 years after complete surgery. To inform patients and care providers in this context of low-quality evidence, the Guideline Working Group therefore prepared recommendations on the basis of expert consensus. Key recommendations are the following: we recommend that all patients with PPGL be considered for genetic testing; we recommend assaying plasma or urinary metanephrines every year to screen for local or metastatic recurrences or new tumours; and we suggest follow-up for at least 10 years in all patients operated on for a PPGL. High-risk patients (young patients and those with a genetic disease, a large tumour and/or a paraganglioma) should be offered lifelong annual follow-up.

© 2016 European Society of Endocrinology.
Eur J Endocrinol. 2016 May;174(5):G1-G10. doi: 10.1530/EJE-16-0033.

わが国の褐色細胞腫疫学調査結果

推計患者数（a）、発生部位と悪性、腫瘍局在、多発の割合（b）、臨床像（c）

組織学的グレードと患者の生存確率

患者の生存期間とGAPP分類の関連性がKaplan-Meier生存曲線で示されている。高分化型（A 、111例）と中分化型（B 、36例）、中分化型（B）と低分化型（C 、16例）、高分化型（A）と低分化型（C）の生存確率には各々有意差がある（p<0.001 、p<0.05 、p<0.001）。
出典
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1: Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma.
著者: Noriko Kimura, Ryoichi Takayanagi, Nae Takizawa, Eiji Itagaki, Takayuki Katabami, Narihiko Kakoi, Hiromi Rakugi, Yukihiro Ikeda, Akiyo Tanabe, Takeshi Nigawara, Sadayoshi Ito, Itaru Kimura, Mitsuhide Naruse, Phaeochromocytoma Study Group in Japan
雑誌名: Endocr Relat Cancer. 2014 Jun;21(3):405-14. doi: 10.1530/ERC-13-0494. Epub 2014 May 6.
Abstract/Text: Phaeochromocytomas (PHEO) and paragangliomas are rare catecholamine-producing tumours. Although 10-30% of these tumours metastasise, histopathological criteria to discriminate malignant from benign tumours have not been established; therefore, reliable histopathological markers predicting metastasis are urgently required. A total of 163 tumours, including 40 metastatic tumours, collected by the Phaeochromocytoma Study Group in Japan (PHEO-J) were analysed using a system called grading system for adrenal phaeochromocytoma and paraganglioma (GAPP). The tumours were scored based on GAPP criteria as follows: histological pattern, cellularity, comedo-type necrosis, capsular/vascular invasion, Ki67 labelling index and catecholamine type. All tumours were scored from 0 to 10 points and were graded as one of the three types: well-differentiated (WD, 0-2 points), moderately differentiated (MD, 3-6 points) and poorly differentiated (PD, 7-10 points). GAPP scores of the non-metastatic and metastatic groups were 2.08±0.17 and 5.33±0.43 (mean±s.e.m., P<0.001) respectively. There was a significant negative correlation between the GAPP score and the interval until metastasis (r=-0.438, P<0.01). The mean number of years until metastasis after the initial operation was 5.5±2.6 years. The study included 111 WD, 35 MD and 17 PD types. The five-year survival of these groups was 100, 66.8 and 22.4% respectively. In addition, negative immunoreactivity for succinate dehydrogenase gene subunit B (SDHB) was observed in 13 (8%) MD or PD tumours and ten of the 13 (77%) had metastases. Our data indicate that a combination of GAPP classification and SDHB immunohistochemistry might be useful for the prediction of metastasis in these tumours.
Endocr Relat Cancer. 2014 Jun;21(3):405-14. doi: 10.1530/ERC-13-0494. ...

褐色細胞腫の診療アルゴリズム

悪性褐色細胞腫の診療アルゴリズム

米国内分泌学会による褐色細胞腫診療ガイドラインで示される本症の診断検査を行うべき状況

出典
imgimg
1: Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
著者: Jacques W M Lenders, Quan-Yang Duh, Graeme Eisenhofer, Anne-Paule Gimenez-Roqueplo, Stefan K G Grebe, Mohammad Hassan Murad, Mitsuhide Naruse, Karel Pacak, William F Young, Endocrine Society
雑誌名: J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42. doi: 10.1210/jc.2014-1498.
Abstract/Text: OBJECTIVE: The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL).
PARTICIPANTS: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), seven experts in the field, and a methodologist. The authors received no corporate funding or remuneration.
EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews.
CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, European Society of Endocrinology, and Americal Association for Clinical Chemistry reviewed drafts of the guidelines.
CONCLUSIONS: The Task Force recommends that initial biochemical testing for PPGLs should include measurements of plasma free or urinary fractionated metanephrines. Consideration should be given to preanalytical factors leading to false-positive or false-negative results. All positive results require follow-up. Computed tomography is suggested for initial imaging, but magnetic resonance is a better option in patients with metastatic disease or when radiation exposure must be limited. (123)I-metaiodobenzylguanidine scintigraphy is a useful imaging modality for metastatic PPGLs. We recommend consideration of genetic testing in all patients, with testing by accredited laboratories. Patients with paraganglioma should be tested for SDHx mutations, and those with metastatic disease for SDHB mutations. All patients with functional PPGLs should undergo preoperative blockade to prevent perioperative complications. Preparation should include a high-sodium diet and fluid intake to prevent postoperative hypotension. We recommend minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas. Partial adrenalectomy is an option for selected patients. Lifelong follow-up is suggested to detect recurrent or metastatic disease. We suggest personalized management with evaluation and treatment by multidisciplinary teams with appropriate expertise to ensure favorable outcomes.
J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42. doi: 10.1210/jc.2014-...