urmjУральский медицинский журналUral Medical Journal2949-4389Ural State Medical University10.52420/2071-5943-2023-22-2-65-73urmj-1229Research ArticleОригинальные статьи | Original articlesOriginal articlesИндекс обновления клеток в дифференциальной диагностике атипической мелкоацинарной пролиферации и аденокарциномы простатыCell renewal index in the differential diagnosis of atypical small acinar proliferation and adenocarcinoma of the prostatehttps://orcid.org/0000-0003-2007-3461ДубА. А.DubA. A.

Анжела Алексеевна Дуб – доктор медицинских наук, доцент

Челябинск

Anzhela A. Dub − Doctor of Science (Medicine), Associated Professor

Chelyabinsk

drow_2390@mail.ruЮжно-Уральский государственный медицинский университетРоссияSouth-Ural State Medical UniversityRussian Federation2023290420232226573Copyright © Дуб А.А., 20232023Дуб А.А.Dub A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.umjusmu.ru/jour/article/view/1229Введение

Введение. Выделение такой диагностической категории как атипическая мелкоацинарная пролиферация предстательной железы (АМАП) определяет необходимость формирования дополнительных подходов к дифференциальной морфологической диагностике с целью своевременного определения аденокарциномы. Индекс обновления клеток (ИОК) активно используется для изучения пролиферации и апоптоза в эпителиальных клетках гормонально зависимых желёз, но при патологии простаты этот критерий не исследован.

Цель исследования – для оптимизации дифференциальной диагностики охарактеризовать индекс обновления клеток при атипической мелкоацинарной пролиферации и аденокарциноме предстательной железы различной степени дифференцировки.

Материалы и методы

Материалы и методы. Исследовано 720 биоптатов простаты от 60 пациентов: 1-я — 15 пациентов с АМАП; 2-я – 15 с аденокарциномой высокой степени дифференцировки; 3-я – 15 с умеренно дифференцированной аденокарциномой; 4-я группа – 15 с низкодифференцированной аденокарциномой. Использован иммуногистохимический метод (Ki-67, CPP32) и непараметрические статистические методы исследования.

Результаты

Результаты. ИОК при АМАП по своим значениям был сопоставим с показателем при высокодифференцированной аденокарциноме (р=0,5). При умереннодифференцированной аденокарциноме ИОК был достоверно выше, чем при АМАП и высокодифференцированной аденокарциноме (р=0,004). Наибольшее увеличение ИОК отмечалось в группе низкодифференцированной аденокарциномы, что было выше и значимо различалось от групп АМАП (p=0,000), высокодифференцированной карциномы (р=0,003) и умеренно дифференцированной карциномы простаты (р=0,000).

Обсуждение

Обсуждение. Настоящее исследование помогло на основании статистического анализа выявить тождество показателей ИОК при АМАП и высокодифференцированной аденокарциноме простаты, что позволяет пополнить ряд морфологических критериев для перевода пациентов из группы неопределённого диагноза АМАП в группу аденокарциномы. Существует необходимость дальнейшего исследования ИОК с многопараметрическим анализом, включающим исследование уровня экспрессии гормонов, участвующих в регуляции клеточного обновления в предстательной железе и связанных с ними ростовых факторов.

Заключение

Заключение. Исследование позволило выявить тождество показателей ИОК при АМАП и высокодифференцированной аденокарциноме простаты, что может пополнить ряд морфологических критериев 

Introduction Singling out such diagnostic category as atypical small acinar proliferation of the prostate (ASAP) determines the necessity of forming additional approaches to differential morphological diagnosis in order to determine adenocarcinoma in time. Cell renewal index (CRI) is actively used to study proliferation and apoptosis in the epithelial cells of hormone-dependent glands, but in prostate pathology this criterion has not been studied.

The aim of the study was to characterize the cell renewal index in atypical small acinar proliferation and prostate adenocarcinoma of different degrees of differentiation in order to optimize differential diagnosis.

Materials and methods We studied 720 prostate biopsy specimens from 60 patients: Group 1 — 15 patients with ASAP; Group 2 − 15 with adenocarcinoma of high-grade of differentiation; Group 3 − 15 with moderately differentiated adenocarcinoma; Group 4 − 15 with low differentiated adenocarcinoma. We used immunohistochemical method (Ki-67, CPP32) and non-parametric statistical methods of investigation.

Results The CRI in ASAP was comparable to that in highly differentiated adenocarcinoma (p=0.5). In moderately differentiated adenocarcinoma the CRI was significantly higher than in ASAP and highly differentiated adenocarcinoma (p=0.004). The greatest increase in CRI was noted in the low-differentiated adenocarcinoma group, which was higher and significantly different from the ASAP (p=0.000), highly differentiated carcinoma (p=0.003) and moderately differentiated prostatic carcinoma (p=0.000) groups.

Discussion On the basis of statistical analysis the present study helped to reveal the identity of CRI parameters in ASAP and highly differentiated adenocarcinoma of the prostat, which allows to add a number of morphological criteria for transferring patients from the group of undetermined diagnosis of ASAP to the group of adenocarcinoma. There is a need for further investigation of CRI with multiparametric analysis including investigation of the expression levels of hormones involved in the regulation of cell renewal in the prostate and growth factors associated with them.

Conclusion The study allowed to reveal the identity of the CRI in ASAP and highly differentiated adenocarcinoma of the prostate, which can supplement a number of morphological criteria for transferring patients from the group of undeterminate diagnosis of ASAP to the group of adenocarcinoma.

атипическая мелкоацинарная пролиферация простатыаденокарцинома простатыиндекс обновления клетокCPP32Ki-67atypical small acinar proliferation of the prostateprostate adenocarcinomacell renewal indexCPP32Ki-67ReferencesParwani AV, Patel A, Zhou M et al. An update on computational pathology tools for genitourinary pathology practice: A review paper from the Genitourinary Pathology Society (GUPS). J Pathol Inform 2022;14:100177. https://doi.org/10.1016/j.jpi.2022.100177.Parwani AV, Patel A, Zhou M et al. An update on computational pathology tools for genitourinary pathology practice: A review paper from the Genitourinary Pathology Society (GUPS). J Pathol Inform 2022;14:100177. https://doi.org/10.1016/j.jpi.2022.100177.Popescu TCT, Stepan AE, Florescu MM, Simionescu CE. Histopathological Study of the Prostate Cancer Growth Patterns in Relation with the Grading Systems. Curr Health Sci J 2022;48(1):95−101. https://doi.org/10.12865/CHSJ.48.01.14.Popescu TCT, Stepan AE, Florescu MM, Simionescu CE. Histopathological Study of the Prostate Cancer Growth Patterns in Relation with the Grading Systems. Curr Health Sci J 2022;48(1):95−101. https://doi.org/10.12865/CHSJ.48.01.14.Humphrey PA.Variants of acinar adenocarcinoma of the prostate mimicking benign conditions Mod Pathol 2018;31(S1):S64−70. http://doi.org/10.1038/modpathol.2017.137.Humphrey PA.Variants of acinar adenocarcinoma of the prostate mimicking benign conditions Mod Pathol 2018;31(S1):S64−70. http://doi.org/10.1038/modpathol.2017.137.Состояние онкологической помощи населению России в 2021 году / под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М. : МНИОИ им. П.А. Герцена − филиал ФГБУ «НМИЦ радиологии» Минздрава России. 2022; 3−9. URL: https://oncology-association.ru/wp-content/uploads/2022/05/sostoyanie-onkologicheskoj-pomoshhi-naseleniyurossii-v-2021-godu.pdf.The state of oncological care for the population of Russia in 2021 / ed. AD Kaprina, VV Starinskogo, AO Shahzadovoj. M. : Gercena MNIOI − filial NMIC radiologii. 2022; 3−9. (In Riss.). URL: https://oncology-association.ru/wp-content/uploads/2022/05/sostoyanie-onkologicheskoj-pomoshhi-naseleniyurossii-v-2021-godu.pdf.Yang C, Humphrey PA. False-Negative Histopathologic Diagnosis of Prostatic Adenocarcinoma Arch Pathol Lab Med 2020;144(3):326−334. http://doi.org/10.5858/arpa.2019-0456-RA.Yang C, Humphrey PA. False-Negative Histopathologic Diagnosis of Prostatic Adenocarcinoma Arch Pathol Lab Med 2020;144(3):326−334. http://doi.org/10.5858/arpa.2019-0456-RA.Zacharouli K, Vageli DP, Koukoulis GK et al. Patient with prostatic adenocarcinoma with plasmacytoid features and an aberrant immunohistochemical phenotype diagnosed by biopsy and a mini-review of plasmacytoid features in the genitourinary system: A case report. Mol Clin Oncol 2022;16(3):67. http://doi.org/10.3892/mco.2022.2500.Zacharouli K, Vageli DP, Koukoulis GK et al. Patient with prostatic adenocarcinoma with plasmacytoid features and an aberrant immunohistochemical phenotype diagnosed by biopsy and a mini-review of plasmacytoid features in the genitourinary system: A case report. Mol Clin Oncol 2022;16(3):67. http://doi.org/10.3892/mco.2022.2500.Verhoef EI, van Cappellen WA, Slotman JA, Kremers GJ et al. Three-dimensional analysis reveals two major architectural subgroups of prostate cancer growth patterns. Mod Pathol 2019;32(7):1032−1041. http://doi.org/10.1038/s41379-019-0221-0.Verhoef EI, van Cappellen WA, Slotman JA, Kremers GJ et al. Three-dimensional analysis reveals two major architectural subgroups of prostate cancer growth patterns. Mod Pathol 2019;32(7):1032−1041. http://doi.org/10.1038/s41379-019-0221-0.Tsampoukas G, Manolas V, Brown D, et al. Atypical small acinar proliferation and its significance in pathological reports in modern urological times. Asian J Urol 2021;9(1):12−17. http://doi.org/10.1016/j.ajur.2021.04.008.Tsampoukas G, Manolas V, Brown D, et al. Atypical small acinar proliferation and its significance in pathological reports in modern urological times. Asian J Urol 2021;9(1):12−17. http://doi.org/10.1016/j.ajur.2021.04.008.Kim H, Kim JK. Clinical strategy of repeat biopsy in patients with atypical small acinar proliferation (ASAP). Sci Rep 2021;11(1). http://doi.org/10.1038/s41598-021-02172-8.Kim H, Kim JK. Clinical strategy of repeat biopsy in patients with atypical small acinar proliferation (ASAP). Sci Rep 2021;11(1). http://doi.org/10.1038/s41598-021-02172-8.Oderda M, Cuneo ASL, Rosazza M et al. Natural history of widespread high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation: should we rebiopsy them all? Scand J Urol 2021;55(9):1−6. http://doi.org/10.1080/21681805.2020.1866659.Oderda M, Cuneo ASL, Rosazza M et al. Natural history of widespread high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation: should we rebiopsy them all? Scand J Urol 2021;55(9):1−6. http://doi.org/10.1080/21681805.2020.1866659.Четер И.Р. Морфологическая характеристика и морфогенез атипичной мелкоацинарной пролиферации предстательной железы с нозологических позиций: диссертация…кандидата медицинских наук: 14.03.02: Курган; 2020; 14−34. URL: https://www.dissercat.com/content/morfologicheskaya-kharakteristika-i-morfogenez-atipichnoi-melkoatsiarnoiproliferatsii-preds.Cheter IR. Morphological characteristics and morphogenesis of atypical small-acinar proliferation of the prostate gland from nosological positions: dissertation ... candidate of medical sciences: 14.03.02: Kurgan; 2020;14−34. (In Russ.). URL: https://www.dissercat.com/content/morfologicheskaya-kharakteristika-i-morfogenez-atipichnoi-melkoatsiarnoiproliferatsii-preds.Дуб А.А., Четер И.Р. Характеристика маркеров клеточного обновления и уровень экспрессии IGF-1R, EGFR, AR при атипической мелкоацинарной пролиферации и аденокарциноме предстательной железы. Уральский медицинский журнал 2020;186(3):23-29. https://doi.org/10.25694/URMJ.2020.03.14.Dub AA, Cheter IR Characterization of cell renewal markers and level of IGF-1R expression, EGFR, AR in atypical melcoacinar proliferation and prostate adenocarcinoma. Ural Medical Journal 2020;186(3):23-29. (In Russ.). https://doi.org/10.25694/URMJ.2020.03.14.Perletti G, Magri V, Vral A et al. Green tea catechins for chemoprevention of prostate cancer in patients with histologically-proven HG-PIN or ASAP. Concise review and meta-analysis. Arch Ital Urol Androl 2019;91:153. http://doi.org/10.4081/aiua.2019.3.153.Perletti G, Magri V, Vral A et al. Green tea catechins for chemoprevention of prostate cancer in patients with histologically-proven HG-PIN or ASAP. Concise review and meta-analysis. Arch Ital Urol Androl 2019;91:153. http://doi.org/10.4081/aiua.2019.3.153.Eryilmaz IE, Vuruskan BA, Kaygısız O et al. RNA-based markers in biopsy cores with atypical small acinar proliferation: Predictive effect of T2E fusion positivity and MMP-2 upregulation for a subsequent prostate cancer diagnosis. Prostate 2019;79:195. http://doi.org/10.1002/pros.23724.Eryilmaz IE, Vuruskan BA, Kaygısız O et al. RNA-based markers in biopsy cores with atypical small acinar proliferation: Predictive effect of T2E fusion positivity and MMP-2 upregulation for a subsequent prostate cancer diagnosis. Prostate 2019;79:195. http://doi.org/10.1002/pros.23724.Navarette MAH, Maier CM, Falzoni R et al. Cellular renovation indices of the human mammary epithelium during the follicular and luteal phases of the menstrual cycle. Brest Cancer Research 2005;7:306−313. http://doi.org/10.1186/bcr994.Navarette MAH, Maier CM, Falzoni R et al. Cellular renovation indices of the human mammary epithelium during the follicular and luteal phases of the menstrual cycle. Brest Cancer Research 2005;7:306−313. http://doi.org/10.1186/bcr994.Bostwick DG, Meiers I. Neoplasma of the prostate. In: Bostwick DG, Cheng L, eds. Urologic Surgical Pathology. Philadelphia, PA: Mosby Elsevier. 2008. pp. 442−579. https://doi.org/10.1016/B978-0-323-01970-5.50011-7.Bostwick DG, Meiers I. Neoplasma of the prostate. In: Bostwick DG, Cheng L, eds. Urologic Surgical Pathology. Philadelphia, PA: Mosby Elsevier. 2008. pp. 442−579. https://doi.org/10.1016/B978-0-323-01970-5.50011-7.Humphrey PA, Moch H, Cubilla AL. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours. Eur Urol 2016;70(1):106−119. https://doi.org/10.1016/j.eururo.2016.02.028.Humphrey PA, Moch H, Cubilla AL. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours. Eur Urol 2016;70(1):106−119. https://doi.org/10.1016/j.eururo.2016.02.028.Epstein JI, Egevad L, Amin MB et al. Grading Committee. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostate Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. Am J Surg Pathol 2016;40(2):244−252. https://doi.org/10.1097/PAS.0000000000000530.Epstein JI, Egevad L, Amin MB et al. Grading Committee. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostate Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. Am J Surg Pathol 2016;40(2):244−252. https://doi.org/10.1097/PAS.0000000000000530.Маслякова Г.Н., Воронина Е.С., Фомкин Р.Н. Морфологические методы исследования в диагностике рака предстательной железы. Фундаментальные исследования 2012;(12−2):426−430.Maslyakova GN, Voronina ES, Fomkin RN Morphological research methods in the diagnosis of prostate cancer. Fundamental’nye issledovanija=Basic Research 2012;(12−2):426−430. (In Russ.).Автандилов Г.Г. Медицинская морфометрия. М : Медицина; 1990. С. 123−125.Avtandilov G.G. Medical morphometry. M : Medicine; 1990. pp. 123−125. (In Russ.).Patel AU, Shaker N, Mohanty S et al. Cultivating Clinical Clarity through Computer Vision: A Current Perspective on Whole Slide Imaging and Artificial Intelligence. Diagnostics (Basel) 2022;12(8):1778. http://doi.org/10.3390/diagnostics12081778.Patel AU, Shaker N, Mohanty S et al. Cultivating Clinical Clarity through Computer Vision: A Current Perspective on Whole Slide Imaging and Artificial Intelligence. Diagnostics (Basel) 2022;12(8):1778. http://doi.org/10.3390/diagnostics12081778.Реброва О.Ю. Статистический анализ медицинских данных. Применение пакета программ Statistica. М : МедиаСфера ; 2002. C. 109−195 URL: https://www.studmed.ru/view/rebrova-oyu-statisticheskiy-analiz-medicinskih-dannyh_0149fe87d1d.html.Rebrova OJu. Statistical analysis of medical data. Application of the program package Statistics. M : MediaSfera ; 2002. pp. 109−195. (In Russ.). URL: https://www.studmed.ru/view/rebrova-oyu-statisticheskiy-analiz-medicinskih-dannyh_0149fe87d1d.html.Malle E, Gil P, Carlos S et al. Atypical small acinar proliferation: Review of a series of 64 patients. Scand J Urol Nephrol 2006;40(4):272−275. https://doi.org/10.1080/00365590600641939.Malle E, Gil P, Carlos S et al. Atypical small acinar proliferation: Review of a series of 64 patients. Scand J Urol Nephrol 2006;40(4):272−275. https://doi.org/10.1080/00365590600641939.Buhmeida A, Pyrhonen S, Laato M, Collan Y. Prognostic factors of prostate cancer. Diagn Pathol 2006;I:4 https://doi.org/10.1186/1746-1596-1-4.Buhmeida A, Pyrhonen S, Laato M, Collan Y. Prognostic factors of prostate cancer. Diagn Pathol 2006;I:4 https://doi.org/10.1186/1746-1596-1-4.Ковылина М.В., Прилепская Е.А., Сергейко И.П. и соавт. Прогностическое значение иммуногистохимических маркеров Ki-67 и р53 после радикальной простатэктомии. Онкоурология 2014;10(1):49−52. https://doi.org/10.17650/1726-9776-2014-10-1-49-52.Kovylina MV, Prilepskaya EA, Sergeiko I.P et al. Prognostic Value Of The Immunohistochemical Markers Ki-67 And P53 After Radical Prostatectomy. Cancer Urology 2014;10(1):49−52. (In Russ.). https://doi.org/10.17650/1726-9776-2014-10-1-49-52.Кудрявцев Г.Ю., Кудрявцева Л.В., Михалева Л.М. c соавт. Иммуногистохимическое исследование экспрессии Ki-67, p53и Notch1 в аденокарциномах предстательной железы различной степени злокачественности. Архив патологии 2020;82(5):42−49. https://doi.org/10.17116/patol20208205142.Kudryavtsev GYu, Kudryavtseva LV, Mikhalyova LM et al. Immunohistochemical study of Ki-67, p53 and Notch1 expressions in prostate cancer of different grades. Arkhiv Patologii 2020;82(5):42−49. (In Russ.). https://doi.org/10.17116/patol20208205142.Verma R, Gupta V, Singh J et al. Significance of p53 and ki-67 expression in prostate cancer. Urol Ann 2015;7(4):488−93. https://doi.org/10.4103/0974-7796.158507.Verma R, Gupta V, Singh J et al. Significance of p53 and ki-67 expression in prostate cancer. Urol Ann 2015;7(4):488−93. https://doi.org/10.4103/0974-7796.158507.Veliiković LJ, Dordević B, Rancić G, Marjanović G. Expression of nuclear Ki-67 antigen in prostatic high grade intraepithelial neoplasia and prostatic carcinoma. Vojnosanit Pregl 2007;64(5):325−330. https://doi.org/10.2298/vsp0705325j.Veliiković LJ, Dordević B, Rancić G, Marjanović G. Expression of nuclear Ki-67 antigen in prostatic high grade intraepithelial neoplasia and prostatic carcinoma. Vojnosanit Pregl 2007;64(5):325−330. https://doi.org/10.2298/vsp0705325j.Moore CK, Karikehalli S, Nazeer T. Prognostic significance of high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation in the contemporary era. J Urol 2005;173:70−72. https://doi.org/10.1097/01.ju.0000148260.69779.c5.Moore CK, Karikehalli S, Nazeer T. Prognostic significance of high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation in the contemporary era. J Urol 2005;173:70−72. https://doi.org/10.1097/01.ju.0000148260.69779.c5.Corsi F, Capradossi F, Pelliccia A, Briganti S et al. Apoptosis as Driver of Therapy-Induced Cancer Repopulation and Acquired Cell-Resistance (CRAC): A Simple In Vitro Model of Phoenix Rising in Prostate Cancer. Int J Mol Sci 2022;23(3):1152. https://doi.org/10.3390/ijms23031152.Corsi F, Capradossi F, Pelliccia A, Briganti S et al. Apoptosis as Driver of Therapy-Induced Cancer Repopulation and Acquired Cell-Resistance (CRAC): A Simple In Vitro Model of Phoenix Rising in Prostate Cancer. Int J Mol Sci 2022;23(3):1152. https://doi.org/10.3390/ijms23031152.Rodríguez-Berriguete G, Galvis L, Fraile B et al. Immunoreactivity to caspase-3, caspase-7, caspase-8, and caspase-9 forms is frequently lost in human prostate tumors. Hum Pathol 2012;43(2):229−237. https://doi.org/10.1016/j.humpath.2011.04.024.Rodríguez-Berriguete G, Galvis L, Fraile B et al. Immunoreactivity to caspase-3, caspase-7, caspase-8, and caspase-9 forms is frequently lost in human prostate tumors. Hum Pathol 2012;43(2):229−237. https://doi.org/10.1016/j.humpath.2011.04.024.Motta VP, Malafaia O, Ribas-Filho JM et al. CASPASE-3 and CD-34 expression in prostate adenocarcinoma. Rev Col Bras Cir 2009;36(3):223−229. https://doi.org/10.1590/s0100-69912009000300008.Motta VP, Malafaia O, Ribas-Filho JM et al. CASPASE-3 and CD-34 expression in prostate adenocarcinoma. Rev Col Bras Cir 2009;36(3):223−229. https://doi.org/10.1590/s0100-69912009000300008.Яковлев А.А., Горозоватский А.Ю., Онуфриев М.В. c соавт. Катепсин мозга способен расщеплять субстрат каспазы. Биохимия 2008;73(3):408−413. https://doi.org/10.1134/s0006297908030140.Yakovlev AA, Gorozovatsky AYu, Onufriev MV et al. Brain cathepsin B cleaves a caspase substrate. Biochemia 2008;73(3):408−413. (In Russ.). https://doi.org/10.1134/s0006297908030140.Acar V, Couto Fernandez FL, Buscariolo FF. et al. Immunohistochemical Evaluation of PARP and Caspase-3 as Prognostic Markers in Prostate Carcinomas. Clin Med Res 2021;19(4):183−191. https://doi.org/10.3121/cmr.2021.1607.Acar V, Couto Fernandez FL, Buscariolo FF. et al. Immunohistochemical Evaluation of PARP and Caspase-3 as Prognostic Markers in Prostate Carcinomas. Clin Med Res 2021;19(4):183−191. https://doi.org/10.3121/cmr.2021.1607.Udensi KU, Tchounwou P.B. Oxidative stress in prostate hyperplasia and carcinogenesis. J Exp Clin Cancer Res 2016;35:139. https://doi.org/10.1186/s13046-016-0418-8.Udensi KU, Tchounwou P.B. Oxidative stress in prostate hyperplasia and carcinogenesis. J Exp Clin Cancer Res 2016;35:139. https://doi.org/10.1186/s13046-016-0418-8.Аllan DJ, Howell A, Roberts SA et al. Reduction in apoptosis relative to mitosis in histologocally normal epithelium accompanies fibrocystic change and carcinoma of the premenopausal human breast J Pathol 1992;167:25−32. https://doi.org/10.1002/path.1711670106.Аllan DJ, Howell A, Roberts SA et al. Reduction in apoptosis relative to mitosis in histologocally normal epithelium accompanies fibrocystic change and carcinoma of the premenopausal human breast J Pathol 1992;167:25−32. https://doi.org/10.1002/path.1711670106.

The authors declare that there are no conflicts of interest present.