Ectopic hormone-producing tumors

Japanese: 異所性ホルモン産生腫瘍

(1) Overview of ectopic hormone-secreting tumors
Definition and Concept Ectopic hormone-producing tumors refer to tumors that produce and secrete hormones that are not produced in the organ in which they are produced. However, highly sensitive hormone measurement methods and gene expression studies have revealed that minute amounts of hormones are produced and secreted in many normal tissues other than the endocrine glands where hormones are normally produced, making it difficult to strictly distinguish between ectopic and orthotopic hormone-producing tumors. For this reason, when a tumor produces an excess of biologically active hormones and symptoms and abnormal biochemical test results are observed, the condition is called ectopic hormonal syndrome. Ectopic hormone syndromes are also known as paraneoplastic syndromes.
)
Classification: The main producing tumors, symptoms, and test findings are shown by hormone in Table 12-11-1. The majority of hormones produced in ectopic hormone production syndromes are peptides. Ectopic production of proteins with complex structures consisting of two subunits that are glycosylated, such as LH, FSH, and TSH, is rare. As for non-peptide hormones, with the exception of lymphomas that produce 1,25-dihydroxyvitamin _D3 , steroid and thyroid hormones require many enzymes for biosynthesis and are only produced in a portion of teratomas.
Some ectopic hormone syndromes that produce pathogenic peptide hormones originate from the embryonic neuroectoderm (neural crest) and have the biochemical characteristic of uptaking amine precursors, decarboxylating them, and converting them into active amines. They are called APUD cells, taking the initials of each cell. It is thought that APUD cells migrate to endodermal organs and become APUDomas, such as small cell lung cancer, pancreatic islet cancer, and bronchial carcinoids, which are prone to mutate into ectopic hormone-producing tumors.
One possible mechanism for hormone production in tumor cells not derived from neural crest is that they undergo dedifferentiation or dysdifferentiation during the tumorigenesis process, resulting in the production of fetal proteins. In the promoter regions upstream of genes where hormone genes are not expressed or are expressed only in small amounts, cytosines may be methylated as an epigenetic change, suppressing gene expression. When demethylation occurs during tumorigenesis, gene expression appears or is enhanced.
Pathophysiology: Compared to hormone secretion from normal endocrine glands, hormone production and secretion from ectopic tumors has significant characteristics.
1) Non-suppression of hormone secretion:
Ectopic hormone production and secretion from tumors is difficult to suppress.
2) Inefficiency of hormone production:
Ectopic hormone production syndromes often occur in advanced cancers because hormone production is inefficient.
3) Insufficient ability to produce mature hormones:
Tumors release inactive precursor or fragment hormones and have reduced production of mature hormone (e.g., secretion of large molecular weight ACTH by ectopic ACTH-secreting tumors).
4) Production of related hormones:
Symptoms of hormonal excess may be due to related hormones (e.g., hypercalcemia due to PTHrP or hypoglycemia due to IGF-II).
Diagnosis: In patients with symptoms of hormone excess or abnormal test results, if a tumor is not detected orthotopically by imaging tests, an ectopic hormone-producing tumor should be considered. The following methods are used to definitively prove a hormone-producing tumor: 1) Confirm immunological hormone production or mRNA in the tumor tissue; 2) Confirm the difference in hormone concentrations between the arteries and veins that nourish the tumor; 3) Prove hormone secretion from the removed tumor tissue; 4) After tumor removal, confirm a decrease in hormone levels in the blood and urine and improvement of clinical signs.
Treatment includes surgery, radiation, and chemotherapy for the causative tumor, as well as symptomatic treatment for hormone excess.
(2)
Ectopic ACTH-producing tumors
Epidemiology: Ectopic ACTH-producing tumors account for approximately 15% of patients with ACTH-dependent Cushing's syndrome. Of ectopic ACTH-producing tumors originating from neuroendocrine cells, small cell lung cancer is the most common, accounting for approximately 50% of all cases, followed by thymic or bronchial carcinoids (approximately 25%), pancreatic islet cell tumors (approximately 10%), other carcinoids (5%), and pheochromocytoma, ovarian adenocarcinoma, or tumors of unknown primary site (unknown primary site) making up the remainder. Ectopic ACTH-producing tumors are slightly more common in men and in those aged between 40 and 60 years.
Pathogenesis Several peptide hormones, including ACTH, are produced from the proopiomeranocortin (POMC) gene by prohormone convertase. In ectopic ACTH-producing tumors, incomplete processing of the precursor protein results in the production and secretion of large ACTH molecules with weak hormonal activity, as well as highly degraded α-melanocyte stimulating hormone (α-MSH), β-MSH, corticotropin-like intermediate lobe peptide (CLIP), γ-LPH, and β-endorphin (β-END).
Secretion of ACTH from pathological tumors is autonomous; serum ACTH does not increase with administration of CRH or AVP, and is often not suppressed even by administration of large amounts of dexamethasone.
Clinical symptoms: Slowly progressing ectopic ACTH-producing tumors due to carcinoids exhibit Cushing's sign, such as moon face and central obesity, but small cell lung cancer progresses rapidly and the nutritional status deteriorates, so Cushing's sign is not clear and patients often exhibit loss of appetite and weight loss. Pigmentation due to ACTH, α-MSH, and β-MSH, and hypokalemic myopathy, hypertension, and lower leg edema due to excessive electrolyte corticoid action are observed. In some carcinoids, the tumor cannot be detected by imaging tests, and periodic Cushing's sign may be observed.
Test results include marked hypokalemia, metabolic alkalosis, hyperglycemia, and elevated plasma ACTH and blood and urinary cortisol levels. The circadian rhythm of plasma ACTH and cortisol is lost, and cortisol is not suppressed by a high-dose dexamethasone suppression test. ACTH is unresponsive to the CRH test and DDAVP test.
Diagnosis and Differential DiagnosisIf Cushing's sign and hypokalemic alkalosis are present, this disease should be suspected, and plasma ACTH and blood and urinary cortisol levels should be measured, along with the above-mentioned loading test. Some carcinoids may show a similar reaction to Cushing's disease, and the specificity is not high. Cushing's disease caused by pituitary adenomas is often a microadenoma, and the tumor location may not be identified, so care must be taken when differentiating it from ectopic ACTH-producing tumors caused by bronchial or thymic carcinoids. Table 12-11-2 shows the differential diagnosis items. An effective method for differentiating between the two is to insert a catheter into the inferior petrosal sinus or cavernous sinus and obtain the peripheral/central ACTH ratio by simultaneously drawing peripheral blood or after CRH loading. Thin slice CT and somatostatin receptor scintigraphy are useful for diagnosing the localization of carcinoids, but there are also occult tumors that cannot be detected by either imaging test.
Treatment and prognosis: There are treatments for the causative tumor and for hypercortisolism. Surgery, radiation, and chemotherapy are available for tumors, but removal is often difficult except for some tumors such as carcinoids. If hypercortisolism persists, the patient's quality of life will decrease due to infections and impaired glucose tolerance, so 11β-hydroxylase inhibitors (metyrapone), 3β-hydroxysteroid dehydrogenase inhibitors (trilostane), or adrenal cortical cytotoxic drugs (mitotane) are administered. If the condition persists for a long time, bilateral adrenalectomy may be performed. The prognosis depends on the treatment of the causative tumor, but the prognosis is poor for tumors other than carcinoids, and approximately half of the deaths from ectopic ACTH-producing tumors are due to severe infections.
(3) Ectopic ADH-producing tumor
Excessive secretion of ADH from ectopic ADH-producing tumors causes dilutional hyponatremia, hypoosmolality, and increased urinary sodium excretion, resulting in water intoxication and the syndrome of inappropriate secretion of ADH (SIADH). It is the second most common paraneoplastic endocrine syndrome after hypercalcemia. Lung cancer accounts for approximately 80% of all ectopic ADH-producing tumors, and of these, approximately 90% are small cell carcinomas. ADH mRNA is often not detected in removed tissue, and SIADH in lung cancer patients is not entirely due to ADH production by tumors; SIADH can also occur when the inhibition of ADH secretion is released due to tumor compression of the vagus nerve, or when insufficient venous return due to an enlarged tumor stimulates the left atrial volume receptor. For pathology, symptoms, and treatment, see section [⇨12-3-4)].
(4)
Ectopic prolactin-producing tumors
Reports of undifferentiated lung cancer, renal cancer, reproductive system tumors, and ovarian teratomas have been reported, but are extremely rare.
(5)
Ectopic GHRH-producing tumors
Epidemiology: Acromegaly can occur in APUDomas such as bronchial carcinoid and pancreatic islet cancer, and GHRH was first identified in human pancreatic islet tumors. Bronchial and digestive tract carcinoids account for approximately 70% of ectopic GHRH production, followed by pancreatic islet cancer. Asymptomatic ectopic GHRH-producing tumors also exist.
Etiology and pathology Due to persistently high levels of GHRH in the blood, the pituitary GH-secreting cells are chronically stimulated and undergo hyperplasia, which leads to high levels of GH and IGF-I in the blood and results in acromegaly.
The clinical symptoms, test results, and diagnostic symptoms are the same as those of acromegaly caused by a pituitary GH-producing tumor. It cannot be differentiated by a loading test, as there is an increase in blood GH and IGF-I and no suppression of blood GH after glucose loading. MRI images do not detect a tumor shadow in the pituitary gland, so a definitive diagnosis requires measurement of blood GHRH.
Treatment involves tumor removal and chemotherapy. If this is ineffective, administration of bromocriptine or somatostatin derivatives may be considered, as in the case of pituitary GH-secreting tumors.
(6)
Ectopic CRH-producing tumors
Epidemiology: Prostate cancer, pheochromocytoma, medullary thyroid carcinoma, mediastinal carcinoid, etc. produce CRH. Some ectopic ACTH-producing tumors also produce small amounts of CRH at the same time.
Etiology and pathology: When ectopic production of CRH is high, pituitary hyperplasia occurs, which increases ACTH secretion.
Clinical symptoms, test results, and diagnosis Symptoms and test findings are similar to those of Cushing's disease and ectopic ACTH-producing tumors. Some cases respond to high-dose dexamethasone tests, CRH tests, and metopirone tests. CRH production in the tumor and high ACTH levels in the inferior petrosal sinus are demonstrated.
Treatment is similar to that for ectopic ACTH-secreting tumors.
(7)
Ectopic hCG-producing tumors
Epidemiology, etiology, and pathogenesis: hCG is produced by trophoblasts and germ cells in many cancers, including ovarian cancer, testicular tumors, hepatoblastoma, large cell lung carcinoma, gastric cancer, and renal cancer.
Clinical symptoms, test results, and diagnosis: If hCG is produced in small amounts or only the α-subunit is produced, there are no symptoms. If large amounts are produced, precocious puberty occurs in boys and gynecomastia occurs in adult men, but women are asymptomatic. Diagnosis is made by elevated serum hCG, plasma α-subunit, and plasma testosterone/estrogen ratio. The diagnosis is confirmed by demonstrating production of hCG and α-subunit by the tumor.
Treatment Tumor removal, chemotherapy and radiation therapy.
(8) Ectopic human chorionic somatomammotropin (hCS)
Ectopic hCS-producing tumor
hCS is also called human placental lactogen (hPL) and is ectopically produced in trophoblastic tumors as well as lung cancer, breast cancer, and liver cancer. Other placental proteins such as hCG may also be produced at the same time. Although it is asymptomatic, gynecomastia is sometimes observed in men.
(9)
Malignancy-associated hypercalcemia
This disease occurs in 5-20% of all patients with malignant tumors and is the most common paraneoplastic endocrine syndrome. The most common causative tumors are lung cancer and renal cancer. The causes of the disease include local osteolytic hypercalcemia (LOH) caused by bone resorption due to widespread bone metastasis and secretion of parathyroid hormone related protein (PTHrP) from the tumor. In terms of histological type, squamous cell carcinoma accounts for more than 65% of PTHrP-producing malignant tumors. For details on the pathology, symptoms, and treatment, please refer to section [⇨12-5-9)].
(10)
ectopic PTH-producing tumor
Hypercalcemia associated with malignant tumors is mostly caused by secretion of PTHrP, but in rare cases, intact PTH-producing tumors are found in lung squamous cell carcinoma, thyroid papillary carcinoma, hepatocellular carcinoma, and other cancers.
(11)
Noninsulin-cell tumor-induced hypoglycemia
Epidemiology : It is known that non-insulinoma non-insulinoma is associated with fasting hypoglycemia. Causing tumors include giant mesenchymal tumors such as giant fibrosarcoma, mesothelioma, and neurofibrosarcoma, as well as hepatocellular carcinoma.
Etiology and pathogenesis: Insulin-like growth factor-II (IGF-II) is thought to be a factor in the development of hypoglycemia in some cases of this disease. Increased glucose utilization due to large tumors is also a cause of hypoglycemia.
Clinical Symptoms, Test Results, and DiagnosisFasting hypoglycemia is the predominant symptom. To rule out insulinoma, it is confirmed that blood insulin levels are suppressed during hypoglycemia. IGF-I, IGF-binding protein-3, and GH are suppressed. Hypokalemia occurs due to insulin-like action. Blood IGF-II is often detected as a larger molecular weight type (11-18 kDa) than the molecular weight detected in normal individuals (7.5 kDa).
Treatment: Tumor removal surgery and chemotherapy are performed. For hypoglycemia, glucose, glucagon, glucocorticoids, etc. are administered.
(12)
Tumor-induced hypophosphatemic osteomalacia
Hypophosphatemic osteomalacia is associated with mesodermal tumors such as hemangioma , fibroma, and giant cell osteosarcoma.
Etiology and pathogenesis Fibroblast growth factor-23 (FGF-23) has been identified as a factor in the development of this disease. For details, see section [⇨12-5-4)].
Clinical symptoms, test results, and diagnosis: Decreased serum phosphorus and 1,25-(OH) ₂ -vitamin D levels, elevated serum alkaline phosphatase, and osteomalacia are present. Phosphate reabsorption from the kidneys is decreased.
TreatmentTumorectomy , chemotherapy, or radiation therapy.
(13)
Ectopic EP-producing tumors
Epidemiology: Renal cell carcinoma accounts for the majority of EP-producing tumors, accounting for approximately 50%, followed by cerebellar hemangioblastoma, accounting for approximately 20%. Tumors associated with von Hippel-Lindau disease are particularly well known.
Clinical symptoms and test results: There is erythrocytosis and blood EP is elevated, but the two do not necessarily correlate.
Treatment: Treatment of tumors and phlebotomy for polycythemia.
(14)
Ectopic calcitonin-producing tumor
Calcitonin is secreted in approximately 80% of cases of APUDoma. Large molecule calcitonin, calcitonin gene-related peptide (CGRP), ACTH, ADH, etc. are often secreted simultaneously, but most cases are asymptomatic.
(15)
Ectopic renin-producing tumors
Small cell lung cancer, pancreatic cancer, and adrenal cortical carcinoma have been reported as extrarenal renin-secreting tumors, but they are rare. Hypertension is observed, and hypokalemia due to secondary hyperaldosteronism is observed.
(16)
Ectopic 1,25-dihydroxyvitamin _D3
Tumors that produce 1α-hydroxylase may be expressed in malignant lymphomas, and 1,25-dihydroxyvitamin D ₃
It produces calcium and phosphorus, which enhances the absorption of calcium and phosphorus from the digestive tract. [Masamitsu Nakazato]
■ References
Brownlee M, Aiello LP, et al: Complications of Diabetes Mellitus. In: Williams Textbook of Endocrinology, 12th ed (Melmed S, Polonsky KS, et al), pp1462-1551, Saunders, Philadelphia, 2011.
Gagel RF: Endocrine manifestations of tumors: ectopic hormone production. In: Cecil Textbook of Medicine, 23rd ed, pp1047-1050, WB Saunders, Philadelphia, 2009.

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

（1）異所性ホルモン産生腫瘍の総論
定義・概念
　異所性ホルモン産生腫瘍とは，その臓器では産生されないホルモンを産生，分泌する腫瘍を指す．しかし，高感度ホルモン測定法や遺伝子発現の研究により，本来，産生されている内分泌腺以外の多くの正常組織でも，ホルモンは微量に産生，分泌されていることが判明し，異所性と正所性のホルモン産生腫瘍は厳密に区別することが困難になってきている．そのため，腫瘍が生物活性のあるホルモンを過剰に産生し，それに基づく症状や生化学的検査値の異常がみられる場合，異所性ホルモン症候群（ectopic hormonal syndrome）という．異所性ホルモン症候群は腫瘍随伴症候群（paraneoplastic syndrome
）の1つでもある．
分類
　おもな産生腫瘍，症状および検査所見をホルモン別に表12-11-1に示す．異所性ホルモン産生症候群で産生されるホルモンの大部分がペプチドである．LH，FSH，TSHのように糖鎖修飾を受け，2つのサブユニットからなる複雑な構造をもつ蛋白の異所性産生はまれである．非ペプチド性のホルモンとして，1,25-ジヒドロキシビタミンD₃を産生するリンパ腫を除いて，ステロイドや甲状腺ホルモンは，生合成に多くの酵素が必要であり，奇形腫の一部に産生が認められるのみである．
病因
　ペプチドホルモンを産生する異所性ホルモン症候群の一部は，胎生期神経外胚葉：神経堤（neural crest）に由来し，アミン前駆体（amine precursor）を取り込み（uptake），脱炭酸（decarboxylation）し，活性アミンにするという生化学的特徴をもつ．各頭文字をとりAPUD系細胞とよばれる．内胚葉器官にAPUD系細胞が移動し，腫瘍化（APUDoma）した小細胞肺癌，膵島癌や気管支カルチノイドなどが異所性ホルモン産生腫瘍に変異しやすいと考えられる．
　神経堤由来以外の腫瘍細胞におけるホルモン産生のメカニズムとして，腫瘍化の過程で脱分化や異分化をきたし，胎児蛋白質を産生することが考えられる．ホルモン遺伝子が発現されないか微量しか発現されない遺伝子上流のプロモーター領域は，エピジェネティックな変化としてシトシンがメチル化されていることがあり，遺伝子発現を抑制している．腫瘍化に伴い脱メチル化されると遺伝子発現が出現または亢進する．
病態生理
　正常の内分泌腺からのホルモン分泌に比べて，異所性腫瘍からのホルモン産生や分泌には大きな特徴がある．
1）ホルモン分泌の非抑制性：
腫瘍からの異所性ホルモン産生や分泌は抑制されにくい．
2）ホルモン産生の非効率性：
ホルモン産生効率が低いため，異所性ホルモン産生症候群は進行癌で発症することが多い．
3）成熟ホルモン産生能の不全：
腫瘍は生理活性のない前駆ホルモンや断片ホルモンを放出し，成熟ホルモン産生能が低下している（例：異所性ACTH産生腫瘍による大分子量ACTHの分泌）．
4）関連ホルモンの産生：
ホルモン過剰症状が関連ホルモン（例：PTHrPによる高カルシウム血症やIGF-Ⅱによる低血糖）によることがある．
診断
　ホルモン過剰の症状や検査値異常を呈する患者で，画像検査で腫瘍が正所性に検出されない場合は，異所性ホルモン産生腫瘍を考慮する．確実なホルモン産生腫瘍の証明は以下のような手法をとる．①腫瘍組織中に免疫学的なホルモン産生やmRNAを確認する．②腫瘍を栄養する動脈と静脈のホルモン濃度較差を確認する．③摘出した腫瘍組織からのホルモン分泌を証明する．④腫瘍摘出後，血中や尿中ホルモン値の低下と臨床徴候の改善を認める．
治療
　原因腫瘍に対する手術，放射線および化学療法による治療とホルモン過剰症に対する対症療法がある．
（2）
異所性ACTH産生腫瘍（ectopic ACTH-producing tumor）
疫学
　ACTH依存性Cushing症候群を呈する患者のうち，異所性ACTH産生腫瘍は約15％を占める．神経内分泌細胞を起源とする異所性ACTH産生腫瘍は，小細胞肺癌が最も多く全体の約50％を占め，ついで胸腺もしくは気管支カルチノイドが約25％，膵島細胞腫が約10％，その他カルチノイドが5％，褐色細胞腫や卵巣腺癌や原発巣不明が残りを占める．異所性ACTH産生腫瘍はやや男性に多く，40歳から60歳に多い．
病因
　proopiomeranocortin（POMC）遺伝子からプロホルモン変換酵素によりACTHを含む複数のペプチドホルモンが生成される．異所性ACTH産生腫瘍では前駆体蛋白質からの不完全なプロセシングにより，ホルモン活性が弱い大分子ACTHや分解が進んだα-melanocyte stimulating hormone（α-MSH）やβ-MSH，corticotropin-like intermediate lobe peptide（CLIP），γ-LPH，β-endorphin（β-END）などが産生，分泌される．
病態
　腫瘍からのACTH分泌は自律性をもち，CRHやAVP投与にも血中ACTHは上昇せず，大量のデキサメタゾン投与でも抑制されないことが多い．
臨床症状
　緩徐に進行するカルチノイドによる異所性ACTH産生腫瘍では，満月様顔貌や中心性肥満などのCushing徴候を呈するが，小細胞肺癌では急速に進行して栄養状態が悪化するため，Cushing徴候は明瞭でなく，食欲不振や体重減少を呈することが多い．ACTH，α-MSH，β-MSHによる色素沈着や過剰な電解質コルチコイド作用による低カリウム性ミオパチーや高血圧，下腿浮腫などが認められる．一部のカルチノイドでは，画像検査で腫瘍が検出できず，周期性Cushing徴候を呈することがある．
検査成績
　著明な低カリウム血症，代謝性アルカローシス，高血糖，血漿ACTHおよび血中や尿中コルチゾール高値がみられる．血漿ACTHやコルチゾールの日内リズムは消失し，大量デキサメサゾン抑制試験でコルチゾールは抑制されない．CRH試験やDDAVP試験では，ACTHは無反応である．
診断・鑑別診断
　Cushing徴候ならびに低カリウム性アルカローシスを伴っていれば本症を疑い，血漿ACTHおよび血中や尿中コルチゾール測定と上記の負荷試験を施行する．一部のカルチノイドでは，Cushing病と同様の反応を示すことがあり，特異性は高くない．下垂体腺腫によるCushing病は微小腺腫のことが多く，腫瘍局在が同定できないことがあり，気管支や胸腺カルチノイドによる異所性ACTH産生腫瘍との鑑別には，注意を要する．表12-11-2に鑑別項目を示す．下錐体静脈洞もしくは海綿静脈洞にカテーテルを挿入し，末梢血と同時採血もしくはCRH負荷後に末梢側/中枢側ACTH値の比を求めて，両者を鑑別する方法が有効である．カルチノイドの局在診断にはthin slice CTやソマトスタチン受容体シンチグラフィが有用であるが，いずれの画像検査でも腫瘍が検出できない潜在性腫瘍もある．
治療・予後
　原因腫瘍に対する治療と高コルチゾール血症に対する治療がある．腫瘍に対しては手術，放射線および化学療法があるが，カルチノイドなど一部の腫瘍以外は摘出困難なことが多い．高コルチゾール血症が持続すれば感染症や耐糖能異常により，患者のQOLが低下するため，11β-ヒドロキシラーゼ阻害薬（メチラポン），3β-ヒドロキシステロイドデヒドロゲナーゼ阻害薬（トリロスタン）や副腎皮質細胞毒性作用薬（ミトタン）を投与する．経過が長期に及ぶ場合は両側副腎摘出を施行する場合もある．予後は原因腫瘍の治療によるが，カルチノイド以外は予後不良であり，異所性ACTH産生腫瘍による死因の約半数は重症感染症である．
（3）異所性ADH産生腫瘍
（ectopic ADH-producing tumor）
　異所性ADH産生腫瘍からADHが過剰に分泌され，希釈性低ナトリウム血症，低浸透圧血症，尿中Na排泄亢進のため，水中毒症状を呈し，ADH不適合分泌症候群（syndrome of inappropriate secretion of ADH：SIADH）をもたらす．腫瘍随伴内分泌症候群としては高カルシウム血症についで頻度が多い．異所性ADH産生腫瘍のうち肺癌が全体の約80％を占め，そのうち約90％は小細胞癌である．摘出組織にADHのmRNAが確認されないことも多く，肺癌患者でのSIADHはすべてが腫瘍のADH産生によるものではなく，腫瘍の迷走神経圧迫によるADH分泌抑制の解除や増大した腫瘍による静脈還流の不足から左心房容積受容体を刺激するためにSIADHをきたすこともある．病態，症状，治療は【⇨12-3-4）】項を参照．
（4）
異所性プロラクチン（PRL）産生腫瘍（ectopic prolactin-producing tumor）
　肺未分化癌，腎癌，生殖器系腫瘍，卵巣奇形腫などが報告されているが，非常にまれである．
（5）
異所性GHRH産生腫瘍（ectopic GHRH-producing tumor）
疫学
　気管支カルチノイドや膵島癌などのAPUDomaに先端巨大症を伴うことがあり，実際にGHRHがはじめて同定されたのはヒト膵島腫瘍からである．異所性GHRH産生のうち気管支や消化管カルチノイドが約70％を占め，ついで膵島癌が多い．無症候性の異所性GHRH産生腫瘍もある．
病因・病態
　血中GHRHの持続高値のため，下垂体のGH分泌細胞が慢性刺激を受け，過形成を呈する．そのため血中GHとIGF-Ⅰの高値をもたらし，先端巨大症を呈する．
臨床症状・検査成績・診断
　症状は下垂体GH産生腫瘍による先端巨大症と同じである．血中GHとIGF-Ⅰの上昇やグルコース負荷後の血中GH非抑制など，負荷試験では鑑別できない．MRI画像では下垂体に腫瘤陰影が検出されず，確定診断には血中GHRHの測定が必要である．
治療
　腫瘍の摘出術，化学療法を実施する．効果が不十分の場合は下垂体GH産生腫瘍と同様にブロモクリプチンやソマトスタチン誘導体の投与も考慮する．
（6）
異所性CRH産生腫瘍（ectopic CRH-producing tumor）
疫学
　前立腺癌，褐色細胞腫，甲状腺髄様癌，縦隔カルチノイドなどがCRHを産生する．また一部の異所性ACTH産生腫瘍も少量のCRHを同時産生する．
病因・病態
　CRHの異所性産生量が多い場合には下垂体過形成を生じ，ACTH分泌を亢進する．
臨床症状・検査成績・診断
　症状や検査所見はCushing病や異所性ACTH産生腫瘍と類似する．高用量デキサメタゾン試験，CRH試験，メトピロン試験に反応する例がある．腫瘍中のCRH産生，下錐体静脈洞内のACTH高値が証明される．
治療
　異所性ACTH産生腫瘍の治療と同様である．
（7）
異所性絨毛性ゴナドトロピン（hCG）産生腫瘍（ectopic hCG-producing tumor）
疫学・病因・病態
　トロホブラストや胚細胞はhCGを産生しており，卵巣癌や睾丸腫瘍，肝細胞芽腫，肺大細胞癌，胃癌，腎癌など多くの癌で産生される．
臨床症状・検査成績・診断
　hCGの産生が少量であったり，α-サブユニットのみの産生であれば無症状である．大量産生では男児で性早熟，成人男性で女性化乳房を認めるが，女性では無症状である．血中hCG，血漿α-サブユニット，血漿テストステロン/エストロゲン比の上昇により診断する．腫瘍でのhCGとα-サブユニット産生を証明し，診断を確定する．
治療
　腫瘍の摘出術，化学療法および放射線療法．
（8）異所性ヒト絨毛性ソマトマンモトロピン
（hCS）
産生腫瘍
（ectopic hCS-producing tumor）
　hCSはヒト胎盤性ラクトーゲン（human placental lactogen：hPL）ともよばれ，栄養膜腫瘍以外に肺癌，乳癌，肝癌などで異所産生される．hCGなどのほかの胎盤性蛋白を同時産生していることもある．無症状であるが，男性でときに女性化乳房を認める．
（9）
悪性腫瘍随伴高カルシウム血症（malignancy-associated hypercalcemia）
　本症は全悪性腫瘍患者の5〜20％に合併し，最も頻度の高い腫瘍随伴内分泌症候群である．原因腫瘍として肺癌と腎癌が多い．病因には，広範な骨転移のため骨吸収による局所性骨融解性高カルシウム血症（local osteolytic hypercalcemia：LOH）と腫瘍からの副甲状腺ホルモン関連蛋白（parathyroid hormone related protein：PTHrP）分泌によるものがある．組織型からみると，PTHrP産生悪性腫瘍の65％以上を扁平上皮癌が占める．病態，症状，治療は【⇨12-5-9）】項を参照．
（10）
異所性PTH産生腫瘍（ectopic PTH-producing tumor）
　悪性腫瘍に伴う高カルシウム血症の原因はPTHrP分泌によるものが大部分を占めるが，まれに肺扁平上皮癌，甲状腺乳頭癌，肝細胞癌などでインタクトPTH産生腫瘍を認める．
（11）
非膵島細胞腫による低血糖症
疫学
　インスリノーマ以外の非膵島細胞腫で空腹時低血糖を伴うことが知られている．原因腫瘍として巨大な線維肉腫，中皮腫，神経線維肉腫などの巨大間葉系腫瘍や肝細胞癌などがある．
病因・病態
　本症の一部は，低血糖の発症因子としてインスリン様成長因子-Ⅱ（IGF-Ⅱ）が関連している．巨大腫瘍によるグルコース利用の増加も低血糖の一因である．
臨床症状・検査成績・診断
　空腹時低血糖症状が主体である．インスリノーマの否定のため，低血糖時に血中インスリン値が抑制されていることを確認する．IGF-Ⅰ，IGF結合蛋白-3，GHは抑制されている．インスリン様作用による低カリウム血症がみられる．血中IGF-Ⅱは正常人で検出される分子量（7.5 kDa）よりも大分子型が検出される（11～18 kDa）ことが多い．
治療
　腫瘍の摘出術や化学療法を施行する．低血糖にはグルコース，グルカゴン，糖質ステロイドなどを投与する．
（12）
腫瘍原性骨軟化症（tumor induced hypophosphatemic osteomalacia）
概念
　血管腫，線維腫，巨細胞性骨肉腫などの中胚葉性腫瘍に低リン血性骨軟化症が合併する．
病因・病態
　本症の発症因子として線維芽細胞増殖因子-23（fibroblast growth factor-23：FGF-23）が同定された．詳細は【⇨12-5-4）】項を参照．
臨床症状・検査成績・診断
　血清リンと1,25-（OH）₂-ビタミンDの低下，血清アルカリホスファターゼ上昇，骨軟化症を呈する．腎臓からのリン再吸収が低下している．
治療
　腫瘍の摘出術，化学療法または放射線療法．
（13）
異所性エリスロポエチン（EP）産生腫瘍（ectopic EP-producing tumor）
疫学
　EP産生腫瘍は腎細胞癌が約50％と最も多く，ついで小脳血管芽腫が約20％を占める．特にvon Hippel Lindau病に伴う腫瘍が有名である．
臨床症状・検査成績
　赤血球増加症があり，血中EPは上昇しているが，必ずしも両者は相関しない．
治療
　腫瘍に対する治療および赤血球増加症に対して瀉血を行う．
（14）
異所性カルシトニン産生腫瘍（ectopic calcitonin-producing tumor）
　APUDomaでは約80％の頻度でカルシトニン産生分泌がある．大分子カルシトニンやカルシトニン遺伝子関連ペプチド（CGRP），ACTH，ADHなどを同時産生していることが多いが，無症候性が大半である．
（15）
異所性レニン産生腫瘍（ectopic renin-producing tumor）
　肺小細胞癌，膵癌，副腎皮質癌などが腎外性レニン産生腫瘍として報告されているが，まれである．高血圧を認め，二次性高アルドステロン血症による低カリウム血症を呈する．
（16）
異所性1,25-ジヒドロキシビタミンD₃
産生腫瘍　悪性リンパ腫では1α-ヒドロキシラーゼを発現することがあり，1,25-ジヒドロキシビタミンD₃
を産生し，消化管からのカルシウムとリンの吸収が亢進する．［中里雅光］
■文献
Brownlee M, Aiello LP, et al: Complications of Diabetes Mellitus. In: Williams Textbook of Endocrinology, 12th ed (Melmed S, Polonsky KS, et al), pp1462-1551, Saunders, Philadelphia, 2011.
Gagel RF: Endocrine manifestations of tumors: ectopic hormone production. In: Cecil Textbook of Medicine, 23rd ed, pp1047-1050, WB Saunders, Philadelphia, 2009.

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