今日の臨床サポート

乳腺症

著者: 本間尚子1) 東邦大学医学部病理学講座

著者: 明石定子2) 昭和大学 乳腺外科

著者: 中村清吾3) 昭和大学医学部外科学講座乳腺外科学部門

監修: 中村清吾 昭和大学医学部外科学講座乳腺外科学部門

著者校正済:2021/11/10
現在監修レビュー中
患者向け説明資料

概要・推奨   

  1. 30~40歳代の成熟期女性に好発する、硬結・腫瘤、疼痛、乳頭異常分泌などの症状を呈する乳腺の良性疾患である。
  1. 月経に伴う症状の周期性、内分泌療法への反応性、実験的エビデンスなどから、乳腺症は、女性ホルモンのアンバランス(エストロゲンのプロゲステロンに対する相対的過剰状態)に起因すると考えられている。
  1. 癌との関係性は低いが、組織診で増殖性病変、特に異型上皮過形成が確認された場合、および乳癌家族歴(第1度近親者)がある場合は、癌になるリスクが高く、厳重な経過観察が必要である。(推奨度1)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
本間尚子 : 特に申告事項無し[2021年]
明石定子 : 特に申告事項無し[2021年]
中村清吾 : 講演料(アストラゼネカ,第一三共,中外製薬),研究費・助成金など(CESデカルト,第一三共,シスメックス,アストラゼネカ,島津製作所,大鵬薬品工業),奨学(奨励)寄付など(エーザイ,コニカミノルタ,大鵬薬品工業,中外製薬)[2021年]
監修:中村清吾 : 講演料(アストラゼネカ,第一三共,中外製薬),研究費・助成金など(CESデカルト,第一三共,シスメックス,アストラゼネカ,島津製作所,大鵬薬品工業),奨学(奨励)寄付など(エーザイ,コニカミノルタ,大鵬薬品工業,中外製薬)[2021年]

改訂のポイント:
  1.  最新の知見に基づき定期レビューを行った(変更なし)。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 乳腺症とは、30~40歳代の成熟期女性に好発する、硬結・腫瘤、疼痛、乳頭異常分泌などの症状を呈する乳腺の良性疾患である。妊娠中・授乳期および閉経後は減少するが、幅広い年齢層にみられる[1]
  1. 乳腺症の発生は、女性ホルモンのアンバランスに起因すると考えられている。
  1. 乳腺疾患のなかでは最も頻度が高いとされるが、正常との線引きなど、その定義・診断基準は明確でない。1つの疾患というよりも、ホルモンバランスの変化や加齢変化に伴う、乳腺の正常からの逸脱として捉えられている。
  1. 病理学的には、乳腺組織の増生、化生、退行などの変化が複雑に絡み合い、多彩な組織像が複合的に局面を形成している状態に相応する。
 
乳腺症の組織像

病理学的には、乳腺組織の増生、化生、退行などの変化が複雑に絡み合った状態で、乳管上皮過形成、乳管乳頭腫症、小葉過形成、閉塞性腺症、硬化性腺症、嚢胞、アポクリン化生など、多彩な組織像が複合的に局面を形成している状態である。
a:嚢胞、アポクリン嚢胞、乳管乳頭腫症など、多彩な組織像が複合的に局面を形成している。
b:アポクリン嚢胞(右上)と乳管乳頭腫症(下方)
c:閉塞性腺症
d:硬化性腺症

出典

img1:  著者提供
 
 
 
  1. 前癌病変であるか否かについては、乳腺症のごく一部に癌になるリスクが高いものがあるが、ほとんどは癌とは無関係と考えられている。
 
  1. 乳腺症の病因(O)
  1. まとめ:好発年齢(30~40歳代)、月経に伴う症状の周期性、内分泌療法への反応性、実験的エビデンスなどから、乳腺症は、女性ホルモンのアンバランス(エストロゲンのプロゲステロンに対する相対的過剰状態)に起因すると考えられている。
  1. 代表事例の説明
  1. 乳腺症患者の約7割は30~40歳代女性だった。腫瘤の2割弱、疼痛の5割強に、月経との関係がみられた[1]
  1. 実験的に乳癌を誘発しやすいラットの系において、相対的エストロゲン優位状態は、乳癌でなく乳腺症類似の病態を惹起した[2]
  1. 血中エストロゲンおよびプロゲステロン濃度を調べたところ、乳腺症患者群では対照群に比し有意に、相対的エストロゲン高値状態にあった[3]
  1. 結論:いずれのエビデンスも、エストロゲンのプロゲステロンに対する相対的過剰状態が、乳腺症の背景にあることを示している。
  1. 追記:文献[1]には、臨床的あるいは病理学的に乳腺症と診断された301例についての臨床・病理学的特徴がまとめられており、「乳腺症」患者の特徴がよく表れている。
  1. 乳腺症の病因が完全に解明されているわけではない。
 
  1. わが国における乳腺症の概念(OJ)
  1. まとめ:乳腺症についての明確な定義は存在しない。“乳腺症カンファレンス”での検討の結果、「乳腺症」についての臨床的概念が提唱された。
  1. 代表事例の説明:わが国では保険の適用上、乳癌でない場合、便宜的に「乳腺症」という診断名がバスケットネーム的に用いられている。このような状況を改善すべく、1994~97年、乳腺専門医21人からなる“乳腺症カンファレンス”が組織され、種々の検討がなされた[1]。病理学的には、7つの構成成分が複合的に局面を形成している状態<図表>、と提案された。各施設で「乳腺症」と病理診断された症例のうち、中央施設の検索でも「乳腺症」とされたのは約1/3で、半数近くの症例は正常範囲内であった[4]。“乳腺症とは、乳房に正常からの逸脱による腫瘤あるいは硬結、乳頭分泌などを認め、しばしば疼痛を伴う臨床的概念である。ただし、腫瘍性、炎症性の病変を除く”という概念が提唱された。
  1. 結論:この概念では、乳腺症の診断には、視触診・画像診断上、明らかな他覚所見が必要とされる。他覚所見のない乳房痛に対する保険病名は「乳房痛」「乳腺症疑い」とすることが提唱されている。
  1. 追記:“乳腺症カンファレンス”での検討内容は1冊の本にまとめられている[5]
  1. “乳腺症カンファレンス”での検討は、マンモグラフィ検診や針生検が普及する以前に行われたため、現状とややずれがあるが、検討内容は詳細で多岐にわたっている。「乳腺症」の定義づけの困難さも示されている。
 
  1. 欧米での乳腺症の捉え方(OG)
  1. まとめ:欧米では1980年代後期より、Aberrations of normal development and involution(ANDI)の概念が発達し、「乳腺症」は1つの疾患というよりも、ホルモンバランスの変化や加齢変化に伴う、乳腺の正常からの逸脱として捉えられるようになっている。現在、fibrocystic breast change(またはcondition)という呼び方が一般的である。
  1. 結論:Hughesらは、剖検例乳腺についての観察などをもとに、種々の良性乳腺病変は、正常な発達および退行性変化からの逸脱として捉えることができる、という概念を提唱した。従来、「乳腺症」とされてきたものも例外ではなく(表、赤字参照)、疾患として対処すべきなのは、異型過形成上皮が認められる場合や疼痛症状が強い場合とした[6]
  1. 追記:上記は良性乳腺病変全般に対して提唱された概念。発達期、成熟期、妊娠・授乳期、退縮期、各々の年齢層に特徴的な正常、逸脱、疾患の状態がまとめられている。
  1. ANDIという用語自体が広く受け入れられているとは言い難いが、概念は適切で、「乳腺症」の概念理解にも役立つ。
 
Aberrations of normal development and involution (ANDI)の概念

種々の良性乳腺病変は、生理的な変化からの逸脱という考え方が主流である。赤字は良性乳腺逸脱状態のうち乳腺症でもみられる所見である。

出典

img1:  Aberrations of normal development and involution (ANDI): a new perspective on pathogenesis and nomenclature of benign breast disorders.
 
 Lancet. 1987 Dec 5;2(8571):1316-9.
 
  1. 乳腺症には癌のリスクが高いか?(推奨度1 O)
  1. まとめ:組織診で異型過形成が確認された乳腺良性疾患症例では、乳癌になるリスクは通常の4.24倍である。異型のない増殖性病変のリスクは1.88倍である。乳癌家族歴は組織像と独立したリスク因子である。
  1. 代表事例の説明:1967~91年に組織診により良性乳腺疾患と診断された女性、9,087人の追跡調査結果(観察期間中央値15年)。組織像の内訳は、非増殖性病変66.7%、異型のない増殖性病変29.6%、異型過形成3.7%で、これまでに707例の癌が確認された。対照群に対する本コホート全体の乳癌リスクは1.56 (95%CI、1.45~1.68)だった。組織像ごとのリスクを比較すると、異型過形成で4.24 (95%CI、3.26~5.41)、異型のない増殖性病変で1.88 (95%CI、1.66~2.12)、非増殖性病変で1.27 (95%CI、1.15~1.41)だった。乳癌の家族歴は、組織像と独立したリスク因子だった。家族歴のない非増殖性病変ではリスクの増加は認められなかった。
  1. 結論:良性乳腺疾患と診断された患者における乳癌のリスク因子は、組織像(増殖性、異型)と乳癌家族歴である。
  1. 追記:上記は文献[7]のまとめであるが、同様の結果は複数の論文で報告されている([8]など)。
  1. 複数の大規模な検討で同様の結果が示されている。増殖性病変(特に異型上皮が認められた場合)あるいは乳癌家族歴がある場合には、厳重なフォローが必要である。なお、本研究の対象は、組織診で良性とされた症例であり、乳腺症症例ではない。組織診で良性とされたもののうち、異型を伴うのは4%(増殖性病変は30%)とされているが、そもそも画像上乳腺症を疑われた症例のうち、組織診にまで至るケースは限られるため、乳腺症のうち癌のリスクが高いものはかなり低いと考えられる。
 
問診・診察のポイント  
  1. 年齢、月経状況、妊娠・授乳歴、乳癌家族歴、症状、病悩期間、症状と月経との関係、薬剤投与状況(特にホルモン剤)などを聴取する。

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文献 

著者: H Yoshida, A Kadota, R Fukunishi, K Matsumoto
雑誌名: J Natl Cancer Inst. 1980 May;64(5):1105-12.
Abstract/Text Effects of neonatal androgenization on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis infemale noninbred Sprague-Dawley rats are reported. Testosterone propionate (1.25 mg) was injected sc into 29 2-day-old rats. At 50 days of age, all rats were given 20 mg of DMBA through a stomach tube. In these androgenized rats, no corpora lutea were found in the ovaries and the induction of mammary carcinoma by DMBA was strongly suppressed, whereas the induction of mammary dysplasia was significantly accelerated in comparison with the neonatally intact controls. Mammary dysplasia in the androgenized group varied widely, with two kinds of macroscopically detectable tumor-forming lesions (solid and cystic) and with microscopic characteristics of acinar adenosis, fibrotic adenosis, fibrosis, intraductal papillary proliferative lesions, and epithelial cysts. The earliest lesions of mammary dysplasia observed were acinar adenosis nodules and microcysts, both of which appeared as multifocal phenomena as early as 25 days after administration of DMBA.

PMID 6767873  J Natl Cancer Inst. 1980 May;64(5):1105-12.
著者: Krzysztof Sieja, Stanisław Stanosz
雑誌名: Ginekol Pol. 2002 Jul;73(7):594-9.
Abstract/Text OBJECTIVE AND STUDY DESIGN: To evaluate the concentrations of prolactin and estrogens in blood sera in women with fibrocystic changes in the breast (FCC).
MATERIAL AND METHODS: The control group consisted of 32 women without any pathological changes in the breast (mean age 44.9 +/- 4.4 y.). The studied group comprised 81 women having FCC (mean age 45.5 +/- 3.5 y.). Both groups were divided into two subgroups according to age: the first subgroup ranged 40-44 y. and the second 45-51 y. The hormonal profiles, namely: prolactin in basal conditions (PRL I), and after metoclopramide-test (PRL II), follitropin (FSH), lutropin (LH), estradiol (E2), progesterone (P) were assayed by means of "bioMerioux" kits. Estrone (E1) was assayed by means of "DBC Diagnostic kits.
RESULTS: In both subgroups of the study group (40-44 and 45-51 y.) a significantly higher (p < 0.001) concentration of prolactin was shown after metoclopramide test, as well as significantly higher percentage increase in prolactin after metoclopramide test (p < 0.001) were shown in comparison with the control group. In age compartment of 40-44 y. in the study group significantly lower (p < 0.05), progesterone-estradiol index (PEL) was found in comparison with the control group. In age compartment of 45-51 y. a progesterone-estradiol index (PEL) in study group was significantly lower (p < 0.05) in comparison with the control group.
CONCLUSION: Functional hyperprolactinemia and relative hyperestrogenism are risk factors of the development concerning fibrocystic changes in the breast.

PMID 12375569  Ginekol Pol. 2002 Jul;73(7):594-9.
著者: L E Hughes, R E Mansel, D J Webster
雑誌名: Lancet. 1987 Dec 5;2(8571):1316-9.
Abstract/Text A framework for understanding and management of benign breast disorders is presented, based on the notion that most breast complaints can be explained as minor aberrations of the normal processes of development, cyclical change, and involution. The generic term ANDI (aberrations of normal development and involution) is introduced to allow breast problems to be placed within an overall framework of pathogenesis; this concept also permits more detailed individual assessment with respect to normality and disease. Fibrocystic disease and its synonyms are discarded in favour of terms that are strictly descriptive of the clinical and/or histological picture.

PMID 2890912  Lancet. 1987 Dec 5;2(8571):1316-9.
著者: Lynn C Hartmann, Thomas A Sellers, Marlene H Frost, Wilma L Lingle, Amy C Degnim, Karthik Ghosh, Robert A Vierkant, Shaun D Maloney, V Shane Pankratz, David W Hillman, Vera J Suman, Jo Johnson, Cassann Blake, Thea Tlsty, Celine M Vachon, L Joseph Melton, Daniel W Visscher
雑誌名: N Engl J Med. 2005 Jul 21;353(3):229-37. doi: 10.1056/NEJMoa044383.
Abstract/Text BACKGROUND: Benign breast disease is an important risk factor for breast cancer. We studied a large group of women with benign breast disease to obtain reliable estimates of this risk.
METHODS: We identified all women who received a diagnosis of benign breast disease at the Mayo Clinic between 1967 and 1991. Breast-cancer events were obtained from medical records and questionnaires. To estimate relative risks, we compared the number of observed breast cancers with the number expected on the basis of the rates of breast cancer in the Iowa Surveillance, Epidemiology, and End Results registry.
RESULTS: We followed 9087 women for a median of 15 years. The histologic findings were nonproliferative lesions in 67 percent of women, proliferative lesions without atypia in 30 percent, and atypical hyperplasia in 4 percent. To date, 707 breast cancers have developed. The relative risk of breast cancer for the cohort was 1.56 (95 percent confidence interval, 1.45 to 1.68), and this increased risk persisted for at least 25 years after biopsy. The relative risk associated with atypia was 4.24 (95 percent confidence interval, 3.26 to 5.41), as compared with a relative risk of 1.88 (95 percent confidence interval, 1.66 to 2.12) for proliferative changes without atypia and of 1.27 (95 percent confidence interval, 1.15 to 1.41) for nonproliferative lesions. The strength of the family history of breast cancer, available for 4808 women, was a risk factor that was independent of histologic findings. No increased risk was found among women with no family history and nonproliferative findings. In the first 10 years after the initial biopsy, an excess of cancers occurred in the same breast, especially in women with atypia.
CONCLUSIONS: Risk factors for breast cancer after the diagnosis of benign breast disease include the histologic classification of a benign breast lesion and a family history of breast cancer.

PMID 16034008  N Engl J Med. 2005 Jul 21;353(3):229-37. doi: 10.1056/N・・・
著者: W D Dupont, D L Page
雑誌名: N Engl J Med. 1985 Jan 17;312(3):146-51. doi: 10.1056/NEJM198501173120303.
Abstract/Text To assess the importance of various risk factors for breast cancer in women with benign proliferative breast lesions, we reevaluated 10,366 consecutive breast biopsies performed in women who had presented at three Nashville hospitals. The median duration of follow-up was 17 years for 3303 women, 1925 of whom had proliferative disease. This sample contained 84.4 per cent of the patients originally selected for follow-up. Women having proliferative disease without atypical hyperplasia had a risk of cancer that was 1.9 times the risk in women with nonproliferative lesions (95 per cent confidence interval, 1.2 to 2.9). The risk in women with atypical hyperplasia (atypia) was 5.3 times that in women with nonproliferative lesions (95 per cent confidence interval, 3.1 to 8.8). A family history of breast cancer had little effect on the risk in women with nonproliferative lesions. However, the risk in women with atypia and a family history of breast cancer was 11 times that in women who had nonproliferative lesions without a family history (95 per cent confidence interval, 5.5 to 24). Calcification elevated the cancer risk in patients with proliferative disease. Although cysts alone did not substantially elevate the risk, women with both cysts and a family history of breast cancer had a risk 2.7 times higher than that for women without either of these risk factors (95 per cent confidence interval, 1.5 to 4.6). This study demonstrates that the majority of women (70 per cent) who undergo breast biopsy for benign disease are not at increased risk of cancer. However, patients with a clinically meaningful elevation in cancer risk can be identified on the basis of atypical hyperplasia and a family history of breast cancer.

PMID 3965932  N Engl J Med. 1985 Jan 17;312(3):146-51. doi: 10.1056/N・・・
著者: D P Rose, A P Boyar, C Cohen, L E Strong
雑誌名: J Natl Cancer Inst. 1987 Apr;78(4):623-6.
Abstract/Text For examination of the effect of a low-fat diet on serum estrogen, progesterone, and gonadotropin levels, 16 patients with cystic breast disease and cyclic mastalgia were studied before dietary intervention and at 2 and 3 months thereafter. Four-day food diaries indicated that total fat intake was reduced from a prediet average of 69 g (35% of total kilocalories/day) to an average of 32 g (21% of total kilocalories) after 3 months. Highly significant reductions (P less than .001) occurred in dietary cholesterol and less changes occurred in protein and total kilocalorie consumption (P less than .05); fiber intakes were not affected. After 3 months on this low-fat diet, there were significant reductions in luteal-phase serum total estrogens (P less than .001), estrone (P less than .005), and estradiol (P less than .01); progesterone, luteinizing hormone, and follicle-stimulating hormone levels were unchanged. Two of the 16 patients were excluded from the hormone statistical analyses because the serum progesterone levels were not consistent with sampling in the luteal phase of the menstrual cycle. It is concluded that a reduction of dietary fat intake to 20% of the total kilocalories will result in significant decreases in circulating estrogens in benign breast disease patients and that this effect is achievable without increasing dietary fiber consumption. Absence of changes in serum progesterone and gonadotropins during the dietary intervention is consistent with altered enterohepatic circulation of estrogens rather than with effects on the pituitary-ovarian axis.

PMID 3104646  J Natl Cancer Inst. 1987 Apr;78(4):623-6.
著者: N F Boyd, V McGuire, P Shannon, M Cousins, V Kriukov, L Mahoney, E Fish, L Lickley, G Lockwood, D Tritchler
雑誌名: Lancet. 1988 Jul 16;2(8603):128-32.
Abstract/Text 21 patients with severe persistent cyclical mastopathy of at least 5 years' duration were randomised to a control group who received general dietary advice or to an intervention group who were taught how to reduce the fat content of their diet to 15% of calories while increasing complex carbohydrate consumption to maintain caloric intake. Both groups were followed for 6 months with food records and measurement of plasma hormone and lipid levels. Severity of symptoms was recorded with daily diaries and patients were assessed at the beginning and end of the study by a physician who was unaware of their dietary regimen. After 6 months there was a significant reduction in the intervention group in the severity of premenstrual breast tenderness and swelling. Physical examination showed reduced breast swelling, tenderness, and nodularity in 6 of 10 patients in the intervention group and 2 of 9 patients in the control group.

PMID 2899188  Lancet. 1988 Jul 16;2(8603):128-32.
著者: N F Boyd, M Cousins, M Beaton, E Fishell, B Wright, E Fish, V Kriukov, G Lockwood, D Tritchler, W Hanna
雑誌名: J Natl Cancer Inst. 1988 Oct 5;80(15):1244-8.
Abstract/Text Despite evidence that dietary fat intake may influence breast cancer risk, there is little information about the effects of dietary fat on the human breast. We have studied the effects of dietary fat on the breast by examining the influence of dietary fat reduction on mammographic dysplasia (nodular or sheetlike areas of radiological density). Subjects with mammographic dysplasia were randomly allocated to a control group, in which they received advice about maintaining a balanced diet (36% of calories as fat), or an intervention group, in which they were taught to reduce dietary fat to a target of 15% of calories. A total of 295 patients consented to randomization, and after 1 year, 20% of the intervention group and 5% of the control group had dropped out (failed to keep appointments and provide nutrient data). The remaining patients closely adhered to the dietary goals of the study as assessed by food records, chemical analysis of duplicate meals, and serum cholesterol measurements. Comparison of mammograms before and after 1 year of dietary fat reduction shows no significant influence on the extent or density of mammographic dysplasia. Surgical biopsies performed in subjects after entry in the study showed five cancers in the control group and two cancers in the intervention group; this total of seven cancers is four times the number expected. These data show that clinical trials of the effects of dietary fat reduction on breast cancer risk are feasible and that long-term compliance with a low-fat diet can be achieved, and they confirm that the patients selected because they had mammographic dysplasia had increased risk of breast cancer.

PMID 3418730  J Natl Cancer Inst. 1988 Oct 5;80(15):1244-8.
著者: N K Horner, J W Lampe
雑誌名: J Am Diet Assoc. 2000 Nov;100(11):1368-80. doi: 10.1016/S0002-8223(00)00383-7.
Abstract/Text Fibrocystic breast conditions, formerly referred to as fibrocystic breast disease, affect about half of all women and typically present as any combination of breast nodularity, swelling, and pain. We reviewed the literature to evaluate evidence supporting nutrition interventions commonly recommended for fibrocystic breast conditions by health care providers. Randomized, controlled studies of the effectiveness of caffeine restriction fail to support any benefit in fibrocystic breast conditions. Similarly, evidence supporting evening primrose oil, vitamin E, or pyridoxine as treatments for the discomforts of fibrocystic breast conditions is insufficient to draw conclusions about effectiveness. Dietary alterations that influence the intermediate markers for fibrocystic breast conditions include low-fat (15% to 20% energy), high-fiber (30 g/day), and soy isoflavone regimens. However, our findings provide no solid evidence for secondary prevention or treatment of fibrocystic breast conditions through a dietary approach. Health care providers should limit recommendations to proven diet therapies supported by randomized, placebo-controlled trials, given the instability inherent in fibrocystic breast conditions and the near 20% placebo effect associated with intervention. Because excessive estrogen or altered sensitivity to estrogen is the dominant theory of etiology, interventions that may modulate endogenous steroid hormones warrant further investigation as potential treatments for symptomatic fibrocystic breast conditions.

PMID 11103660  J Am Diet Assoc. 2000 Nov;100(11):1368-80. doi: 10.1016・・・
著者: Thomas E Rohan, Abdissa Negassa, Bette Caan, Rowan T Chlebowski, J David Curb, Mindy Ginsberg, Dorothy S Lane, Marian L Neuhouser, James M Shikany, Sylvia Wassertheil-Smoller, David L Page
雑誌名: Cancer Prev Res (Phila). 2008 Sep;1(4):275-84. doi: 10.1158/1940-6207.CAPR-08-0003. Epub 2008 Jul 9.
Abstract/Text Modifiable factors, including diet, might alter breast cancer risk. We used the Women's Health Initiative Dietary Modification trial to test the effect of the intervention on risk of benign proliferative breast disease, a condition associated with increased risk of, and considered to be on the pathway to, invasive breast cancer. The Women's Health Initiative Dietary Modification trial was a randomized, controlled, primary prevention trial conducted in 40 U.S. clinical centers from 1993 to 2005. A total of 48,835 postmenopausal women, ages 50 to 79 years, without prior breast cancer, were enrolled. Participants were randomly assigned to the dietary modification intervention group or to the comparison group. The intervention was designed to reduce total dietary fat intake to 20% of total energy intake, and to increase fruit and vegetable intake to > or =5 servings/d and intake of grain products to > or =6 servings/d, but resulted in smaller, albeit significant, changes in practice. Participants had biennial mammograms and regular clinical breast exams. We identified women who reported breast biopsies free of cancer, obtained the histologic sections, and subjected them to standardized central review. During follow-up (average, 7.7 years), 570 incident cases of benign proliferative breast disease were ascertained in the intervention group and 793 in the comparison group. The hazard ratio for the association between dietary modification and benign proliferative breast disease was 1.09 (95% confidence interval, 0.98-1.23). Risk varied by levels of baseline total vitamin D intake but it varied little by levels of other baseline variables. These results suggest that a modest reduction in fat intake and increase in fruit, vegetable, and grain intake do not alter the risk of benign proliferative breast disease.

PMID 19138971  Cancer Prev Res (Phila). 2008 Sep;1(4):275-84. doi: 10.・・・
著者: J P Minton, H Abou-Issa, N Reiches, J M Roseman
雑誌名: Surgery. 1981 Aug;90(2):299-304.
Abstract/Text The results of this study show that the consumption of methylxanthines through dietary sources appears to be associated with the etiologic development of benign fibrocystic disease in the American woman. Complete abstention from methylxanthine consumption resulted in complete resolution of the disease in 82.5% and significant improvement in 15% of those studied. Thus 97.5% showed clinical benefit from total methylxanthine abstention. The results of a clinical questionnaire answered by 500 women consuming methylxanthines, one half of whom had fibrocystic breast disease, suggest that women with fibrocystic disease may have a genetic predisposition for both benign breast disease and cancer. Biochemical studies implicate increased sensitivity of the adenylate cyclase system to catecholamines in patients with fibrocystic disease. Methylxanthines are known to increase circulating catecholamines.

PMID 7256542  Surgery. 1981 Aug;90(2):299-304.
著者: V L Ernster, L Mason, W H Goodson, E A Sickles, S T Sacks, S Selvin, M E Dupuy, J Hawkinson, T K Hunt
雑誌名: Surgery. 1982 Mar;91(3):263-7.
Abstract/Text There is considerable interest in the potential effect on benign disease of a diet free of methylxanthines (caffeine, theophylline, and theobromine) found in coffee, tea, colas, and chocolate. We randomly assigned 158 women who presented with a breast concern either to a group encouraged to abstain from methylxanthine-containing foods and beverages or to a group who received no dietary recommendations (controls). At the initial visit each patient's sociomedical history and data on methylxanthine consumption were obtained by interview, and clinically palpable breast findings were graded on a scale of 0 to 4 (no nodularity to confluent hard "dysplasia") for each quadrant of both breasts. On the follow-up visit approximately 4 months later similar information was obtained. Mammograms were taken at both visits for a subset of women in each group. We found a statistically significant reduction in clinically palpable breast findings in the abstaining group as compared with controls, but the absolute change was minor and may be of little clinical significance. Comparison of before-after mammograms offered little support for the methylxanthine hypothesis. There was no relation between clinically palpable breast finding scores at initial examination and caffeine consumption levels reported at that time.

PMID 7058508  Surgery. 1982 Mar;91(3):263-7.
著者: S S Allen, D G Froberg
雑誌名: Surgery. 1987 Jun;101(6):720-30.
Abstract/Text A single-blind, randomized clinical trial of 56 female subjects was conducted to determine whether decreased consumption of caffeine decreases breast pain/tenderness or nodularity in patients with suspected benign proliferative breast disease. The subjects were randomly assigned to one of three groups--a control group (no dietary restrictions), a placebo group (cholesterol-free diet), and an experimental group (caffeine-free diet). At the initial examination, the subjects reported on the presence of breast pain, the degree to which pain affects daily activities, the frequency of pain, the degree of pain associated with breast examinations, and the degree of pain associated with close-fitting clothing. Subjects were then examined and the four quadrants of each breast were rated on a scale of 0 to 3 (0 = normal, fatty tissue, 1 = little seedy bumps or fine nodularity, 2 = discrete nodules or ropy tissue, 3 = confluent areas, hard or soft masses). Subjects in all three groups returned for 2- and 4-month follow-up examinations. Total nodularity scores, degree of pain/tenderness, and compliance with dietary restrictions were analyzed. The data showed that decreased caffeine consumption did not result in a significant reduction of palpable breast nodules or in a lessening of breast pain/tenderness.

PMID 3296263  Surgery. 1987 Jun;101(6):720-30.
著者: T E Rohan, M G Cook, A J McMichael
雑誌名: Int J Epidemiol. 1989 Sep;18(3):626-33.
Abstract/Text The relationship between methylxanthine intake (caffeine, theobromine and theophylline) and risk of benign proliferative epithelial disorders (BPED) of the breast was examined in a case-control study conducted in Adelaide, South Australia. The study involved 383 cases with biopsy-confirmed BPED, 192 controls whose biopsy did not show epithelial proliferation, and 383 unbiopsied community controls individually matched to cases on age and area of residence. Overall, there was relatively little variation in risk of BPED with total methylxanthine intake, or with intake of caffeine or theophylline, while there was a positive association between theobromine intake and risk of BPED, but only when cases were compared with biopsy controls. Total methylxanthine intake was positively associated with risk of BPED showing severe atypia, but the trend in risk was statistically significant only when community controls formed the comparison group. These data do not provide strong support for an association between methylxanthine intake and risk of BPED.

PMID 2681017  Int J Epidemiol. 1989 Sep;18(3):626-33.
著者: W R Ghent, B A Eskin, D A Low, L P Hill
雑誌名: Can J Surg. 1993 Oct;36(5):453-60.
Abstract/Text OBJECTIVE: To determine the response of patients with fibrocystic breast disease to iodine replacement therapy.
DESIGN: Review of three clinical studies beginning in 1975: an uncontrolled study with sodium iodide and protein-bound iodide; a prospective, control, crossover study from iodide to molecular iodine; and a prospective, control, double-blind study with molecular iodine.
SETTING: University affiliated breast-treatment clinics.
PATIENTS: Study 1: 233 volunteers received sodium iodide for 2 years and 588 received protein-bound iodide for 5 years. Study 2: the treatment of 145 patients from study 1 treated with protein-bound iodide for several months who still had symptoms was switched to molecular iodine 0.08 mg/kg; 108 volunteers were treated initially with molecular iodine. Study 3: 23 patients received molecular iodine, 0.07 to 0.09 mg/kg body weight; 33 received an aqueous mixture of brown vegetable dye and quinine. The numbers in study 2 increased over the review period so that 1365 volunteers were being treated with molecular iodine by 1989.
INTERVENTIONS: All patients in study 3 had pre- and post-treatment mammography and measurement of serum triiodothyronine, thyroxine and thyroid-stimulating hormone levels.
MAIN OUTCOME MEASURES: Subjective evaluation--freedom from pain--and objective evaluation--resolution of fibrosis.
RESULTS: Study 1: 70% of subjects treated with sodium iodide had clinical improvement in their breast disease, but the rate of side effects was high; 40% of patients treated with protein-bound iodide had clinical improvement. Study 2: 74% of patients in the crossover series had clinical improvement, and objective improvement was noted in 72% of those who received molecular iodine initially. Study 3: in the treatment group 65% had subjective and objective improvement; in the control group there was a subjective placebo effect in 33% and an objective deterioration of 3%.
CONCLUSIONS: The fibrocystic breast reacts differently to sodium iodide, protein-bound iodide and molecular iodine. Molecular iodine is nonthyrotropic and was the most beneficial.

PMID 8221402  Can J Surg. 1993 Oct;36(5):453-60.
著者: Jack H Kessler
雑誌名: Breast J. 2004 Jul-Aug;10(4):328-36. doi: 10.1111/j.1075-122X.2004.21341.x.
Abstract/Text A randomized, double-blind, placebo-controlled, multicenter clinical trial was conducted with 111 otherwise healthy euthyroid women with a history of breast pain. Patients had to document moderate or severe breast pain by recording a score > or =5 on a visual analog scale (VAS) of pain for > or =6 days per cycle and had to present with fibrosis involving at least 25% of both breast surfaces. Subjects could not be effectively treated with more conservative measures such as local heat or nonprescription analgesics. There was not a statistically significant difference in the dropout rate for patients on placebo (11.8%), 1.5 mg/day (31.3%), 3.0 mg/day (18.4%), or 6.0 mg/day (25%) of molecular iodine for 6 months. Physicians assessed breast pain, tenderness, and nodularity each cycle; patients assessed breast pain and tenderness with the Lewin breast pain scale at 3-month intervals and with a VAS at each cycle. A statistically significant improvement (p < 0.01) associated with dose was observed in the Lewin overall pain scale for all treated groups compared to placebo. Reductions in all three physician assessments were observed in patients after 5 months of therapy in the 3.0 mg/day (7/28; 25%) and 6.0 mg/day (15/27; 18.5%) treatment groups, but not the 1.5 mg/day or placebo group. Patients recorded statistically significant decreases in pain by month 3 in the 3.0 and 6.0 mg/day treatment groups, but not the 1.5 mg/day or placebo group; more than 50% of the 6.0 mg/day treatment group recorded a clinically significant reduction in overall pain. All doses were associated with an acceptable safety profile. No dose-related increase in any adverse event was observed.

PMID 15239792  Breast J. 2004 Jul-Aug;10(4):328-36. doi: 10.1111/j.107・・・
著者: Lyn Patrick
雑誌名: Altern Med Rev. 2008 Jun;13(2):116-27.
Abstract/Text Iodine deficiency is generally recognized as the most commonly preventable cause of mental retardation and the most common cause of endocrinopathy (goiter and primary hypothyroidism). Iodine deficiency becomes particularly critical in pregnancy due to the consequences for neurological damage during fetal development as well as during lactation. The safety of therapeutic doses of iodine above the established safe upper limit of 1 mg is evident in the lack of toxicity in the Japanese population that consumes 25 times the median intake of iodine consumption in the United States. Japan's population suffers no demonstrable increased incidence of autoimmune thyroiditis or hypothyroidism. Studies using 3.0- to 6.0-mg doses to effectively treat fibrocystic breast disease may reveal an important role for iodine in maintaining normal breast tissue architecture and function. Iodine may also have important antioxidant functions in breast tissue and other tissues that concentrate iodine via the sodium iodide symporter.

PMID 18590348  Altern Med Rev. 2008 Jun;13(2):116-27.
著者: Jane Teas, Thomas G Hurley, James R Hebert, Adrian A Franke, Daniel W Sepkovic, Mindy S Kurzer
雑誌名: J Nutr. 2009 May;139(5):939-44. doi: 10.3945/jn.108.100834. Epub 2009 Mar 25.
Abstract/Text Seaweed and soy foods are consumed daily in Japan, where breast cancer rates for postmenopausal women are significantly lower than in the West. Likely mechanisms include differences in diet, especially soy consumption, and estrogen metabolism. Fifteen healthy postmenopausal women participated in this double-blind trial of seaweed supplementation with soy challenge. Participants were randomized to 7 wk of either 5 g/d seaweed (Alaria) or placebo (maltodextrin). During wk 7, participants also consumed a daily soy protein isolate (2 mg isoflavones/kg body weight). After a 3-wk washout period, participants were crossed over to the alternate supplement schedule. There was an inverse correlation between seaweed dose (mg/kg body weight) and serum estradiol (E2) (seaweed-placebo = y = -2.29 x dose + 172.3; r = -0.70; P = 0.003), [corrected] which was linear across the range of weights. Soy supplementation increased urinary daidzein, glycitein, genistein, and O-desmethylangolensin (P = 0.0001) and decreased matairesinol and enterolactone (P < 0.05). Soy and seaweed plus soy (SeaSoy) increased urinary excretion of 2-hydroxyestrogen (2-OHE) (P = 0.0001) and the ratio of 2-OHE:16alpha-hydroxyestrone (16alphaOHE(1)) (P = 0.01). For the 5 equol excretors, soy increased urinary equol excretion (P = 0.0001); the combination of SeaSoy further increased equol excretion by 58% (P = 0.0001). Equol producers also had a 315% increase in 2:16 ratio (P = 0.001) with SeaSoy. Seaweed favorably alters estrogen and phytoestrogen metabolism and these changes likely include modulation of colonic bacteria.

PMID 19321575  J Nutr. 2009 May;139(5):939-44. doi: 10.3945/jn.108.100・・・
著者: H Funahashi, T Imai, T Mase, M Sekiya, K Yokoi, H Hayashi, A Shibata, T Hayashi, M Nishikawa, N Suda, Y Hibi, Y Mizuno, K Tsukamura, A Hayakawa, S Tanuma
雑誌名: Jpn J Cancer Res. 2001 May;92(5):483-7.
Abstract/Text To investigate the chemopreventive effects of seaweed on breast cancer, we have been studying the relationship between iodine and breast cancer. We found earlier that the seaweed, wakame, showed a suppressive effect on the proliferation of DMBA (dimethylbenz(a)anthracene)-induced rat mammary tumors, possibly via apoptosis induction. In the present study, powdered mekabu was placed in distilled water, and left to stand for 24 h at 4 degrees C. The filtered supernatant was used as mekabu solution. It showed an extremely strong suppressive effect on rat mammary carcinogenesis when used in daily drinking water, without toxicity. In vitro, mekabu solution strongly induced apoptosis in 3 kinds of human breast cancer cells. These effects were stronger than those of a chemotherapeutic agent widely used to treat human breast cancer. Furthermore, no apoptosis induction was observed in normal human mammary cells. In Japan, mekabu is widely consumed as a safe, inexpensive food. Our results suggest that mekabu has potential for chemoprevention of human breast cancer.

PMID 11376555  Jpn J Cancer Res. 2001 May;92(5):483-7.
著者: Mei Zhou, Natalia Wege, Huakang Gu, Li Shang, Jian Li, Johannes Siegrist
雑誌名: J Occup Health. 2010;52(6):361-6. Epub 2010 Oct 7.
Abstract/Text OBJECTIVES: To explore the separate and combined effects of work and family stress on menstrual disorders and fibrocystic changes in Chinese working women.
METHODS: Data were obtained from a cross-sectional study of 1,642 female railway workers. The Effort-Reward Imbalance Questionnaire and Family Stress Scale were used to measure work stress and family stress, respectively; the menstrual and breast conditions were evaluated by gynecologic interview and a medical examination. Multivariate log-binomial regression was performed to analyze the associations.
RESULTS: Menstrual disorders were found in 59.3% of female workers, and 54.8% had fibrocystic changes. The risk of menstrual disorders was significantly elevated with respect to work and family stress. The highest risk was found in the group with combined exposure to both work and family stress (RR with 95% CI 1.33 (1.18-1.49)). No significant association between stress and fibrocystic changes was observed.
CONCLUSIONS: Menstrual disorders were associated with stress from work and family life, but not fibrocystic changes, in working women. Tailored intervention measures reducing the burden of stressful psychosocial work and family environment are needed to improve women's reproductive well-being.

PMID 20944439  J Occup Health. 2010;52(6):361-6. Epub 2010 Oct 7.
著者: G S Berkowitz, J L Kelsey, V A LiVolsi, M J Merino, T R Holford, N G Hildreth, S Ort, T Z O'Connor, C White
雑誌名: Int J Cancer. 1984 Oct 15;34(4):443-9.
Abstract/Text In a hospital-based case-control study of 590 women with biopsy-proven fibrocystic breast disease and 1,018 control women with other surgical conditions, no linear relationship was evident between the use of oral contraceptives or of estrogen replacement therapy and the degree of epithelial atypia of the fibrocystic lesions. Case-control and intracase comparisons suggested that oral contraceptive use might be associated with an increased occurrence of sclerosing adenosis among the premenopausal women and of gross cysts among the postmenopausal women. Estrogen replacement therapy, which was positively associated with fibrocystic breast disease as a whole among the post-menopausal women, was most frequently used among the cases whose biopsy specimens exhibited gross cysts, papillomatosis or papillary hyperplasia.

PMID 6490201  Int J Cancer. 1984 Oct 15;34(4):443-9.
著者: L J Hofseth, A M Raafat, J R Osuch, D R Pathak, C A Slomski, S Z Haslam
雑誌名: J Clin Endocrinol Metab. 1999 Dec;84(12):4559-65. doi: 10.1210/jcem.84.12.6194.
Abstract/Text The relative effects of postmenopausal hormone replacement therapy (HRT) with estrogen alone vs. estrogen+progestin on breast cell proliferation and on breast cancer risk are controversial. A cross-sectional observational study was carried out to examine the proliferative effects of HRT with estrogen or estrogen plus the progestin, medroxyprogesterone acetate, in breast tissue of postmenopausal women. Benign breast biopsies from 86 postmenopausal women were analyzed with antiproliferating cell nuclear antigen (anti-PCNA) and Ki67 antibodies to measure relative levels of cell proliferation. Epithelial density and estrogen and progesterone receptor status were also determined. The women were categorized either as users of: 1) estrogen (E) alone; 2) estrogen+medroxyprogesterone acetate (E+P); or 3) no HRT. Compared with no HRT, the breast epithelium of women who had received either E+P or E alone had significantly higher PCNA proliferation indices, and treatment with E+P had a significantly higher index (PCNA and Ki67) than treatment with E alone. Breast epithelial density was significantly greater in postmenopausal women treated with E and E+P, compared with no HRT. Thus, the present study shows that postmenopausal HRT with E+P was associated with greater breast epithelial cell proliferation and breast epithelial cell density than E alone or no HRT. Furthermore, with E+P, breast proliferation was localized to the terminal duct-lobular unit of the breast, which is the site of development of most breast cancers. Further studies are needed to assess the possible association between the mitogenic activity of progestins and breast cancer risk.

PMID 10599719  J Clin Endocrinol Metab. 1999 Dec;84(12):4559-65. doi: ・・・
著者: D Cyrlak, C H Wong
雑誌名: AJR Am J Roentgenol. 1993 Dec;161(6):1177-83. doi: 10.2214/ajr.161.6.8249722.
Abstract/Text Increasing numbers of postmenopausal women are undergoing hormonal replacement therapy. In this pictorial essay, we present the spectrum of mammographic changes seen in these women. These changes include symmetric and asymmetric increase in breast density, increase in size of fibroadenomas, and development or increase in size of cysts. Our examples illustrate that differentiation of hormonal therapy changes from neoplasm can occasionally be problematic when a focal density or mass is seen on mammograms. Furthermore, reexamination of published reports and our cases suggests that treatment with estrogen alone promotes enlargement of cysts and fibroadenomas, whereas treatment with a combination of estrogen and progesterone is more likely to be associated with diffuse increase in density.

PMID 8249722  AJR Am J Roentgenol. 1993 Dec;161(6):1177-83. doi: 10.2・・・

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