The aetiology and pathogenesis of human breast cancer

Whilst investigators have clearly shown that non-hereditary factors dominate the aetiology of human breast cancer, they have failed to identify quantitatively important causes, and prospects for prevention remain indeed. However, progress in epidemiological and basic research has taken place during the last few years. Current evidence suggests that breast cancer may be affected by the intra-uterine environment, that exposures during adolescence are particularly important, and that pregnancy has a dual effect on breast cancer risk: an early increase followed by long-term protection. Great variation exists in the structural development of the breast ductal system already in the newborn — and by inference in utero — and a pregnancy induces permanent structural changes in the mammary gland. We suggest that these observations fit into an aetiological model with the following key components: (1) breast cancer risk depends on the number of cells at risk, the susceptibility of individual cells to malignant transformation, and on the degree of cellular proliferation, notably cells which can act as founders of breast cancer; (2) the number of target cells is determined by the hormonal environment mainly early in life, perhaps already in utero; (3) in adult life, hormones which are non-genotoxic, increase breast cancer risk by increasing selective cell proliferation and thus number of target cells and the risk of retention of spontaneous somatic mutations; (4) while a pregnancy stimulates the growth of already malignant cells to malignant transformation (and thereby entails a short-term risk increase) the dominating long-term protection occurs due to permanent structural changes, terminal differentiation and perhaps decreased cell proliferation and carcinogen-binding in combination.     

Primary angiosarcoma of the breast complicated by the syndrome of disseminated intravascular coagulation (DIC): Case report and literature review

Primary angiosarcoma of the breast (PAB) accounts for 0.04% of all breast malignant tumors. It affects young women usually at third or fourth decades of life. PAB clinically manifests as a painless, movable mass with sharp limits. A bluish red discoloration of the overlying skin is often observed. Enlargement of axillary lymph nodes generally does not occur.Angiosarcoma of the breast has a very poor prognosis due to the tendency to metastasize haematogenously and high frequency of local recurrence.Mastectomy and chemotherapy are preferable treatment choices.This paper presents a case of primary angiosarcoma of the breast with a syndrome of disseminated intravascular coagulation (DIC).     

Lobular ectopic breast carcinoma: A case-report

In about 1–2% of the population an incomplete regression of the embryonic mammary line occurs, which may result in the presence of ectopic breast tissue. An ectopic breast tissue carcinoma is a rare entity. The authors present a case-report of a 51-year-old female patient, with a lobular carcinoma in an axillary ectopic breast tissue submitted to surgery and adjuvant radiotherapy.     

Partial breast irradiation techniques in early breast cancer

Whole breast irradiation represents an integral part of combined breast-conserving treatment of early breast cancer. A new concept includes replacing traditionally fractionated whole breast postoperative radiotherapy by accelerated partial breast irradiation. The latter involves a variety of techniques and may be applied intraoperatively or shortly after the surgery. The intraoperative techniques include photon or electron external beam irradiation and interstitial high dose rate (HDR) brachytherapy, whereas the postoperative techniques comprise interstitial brachytherapy, be it HDR, pulse dose rate (PDR) or low dose rate (LDR), intracavitary brachytherapy and external beam radiotherapy using electrons, photons or protons. This article presents accelerated partial breast irradiation techniques, ongoing phase III trials evaluating their value and recommendations for clinical practice.     

Rare lymphoid malignancies of the breast: a report of two cases illustrating potential diagnostic pitfalls

Breast involvement by lymphoma is uncommon and poses challenges in diagnosis. Lymphomas may clinically, radiologically, and morphologically mimic both benign and neoplastic conditions. We describe two cases of lymphoid malignancies predominantly involving the breast, both presenting diagnostic dilemmas. The first case, ALK-negative anaplastic large-cell lymphoma involving a seroma associated with a breast implant, is an emerging clinicopathologic entity. Anaplastic large-cell lymphoma has been identified in association with breast implants and seroma formation relatively recently. The second case, hairy cell leukemia involving the breast and ipsilateral axillary sentinel lymph node, is, to our knowledge, the first reported case of hairy cell leukemia involving the breast at the time of diagnosis. While a localized bone lesion was present at time of diagnosis, bone marrow involvement was relatively mild in comparison to that seen in the breast and lymph node. In the first case, lymphoma occurred in a clinical setting where malignancy was unsuspected, highlighting the importance of careful morphologic evaluation of paucicellular samples, as well as awareness of rare clinicopathologic entities, in avoiding a misdiagnosis of a benign inflammatory infiltrate. In the second case, the lymphoid neoplasm exhibited classic morphologic and immunophenotypic features, but presented at an unusual site of involvement. Knowledge of the patient''s concurrent diagnosis of hairy cell leukemia involving the bone marrow and bone helped avoid a misdiagnosis of carcinoma rather than lymphoma.     

Hypofractionated radiotherapy for early breast cancer: Review of phase III studies

Breast-conserving surgery including whole breast irradiation has long been a recommended procedure for early breast cancer. However, conventionally fractionated radiotherapy requires a lengthy hospitalisation or prolonged commuting to a hospital for radiotherapy. In recent years, hypofractionated radiotherapy has increasingly been used. This method involves higher fraction doses (above 2 Gy) as compared to conventional radiotherapy, so the total dose can be delivered in fewer fractions and in a shorter overall treatment time. This review aims at presenting most important outcomes of four randomised studies comparing conventional and hypofractionated radiotherapy schemes including a total of 7000 patients. These studies have not shown apparent differences in treatment efficacy, incidence of late post-radiotherapy complications or cosmetic effects during a 5–10 year follow-up, but longer observation is warranted to fully evaluate the safety of this method. Currently, major societies consider modestly hypofractionated radiotherapy schemes as a routine management in selected groups of patients undergoing breast-conserving surgery. However, this method should be used cautiously in patients with lymph node metastases, big breasts, receiving chemotherapy or trastuzumab, or those under 50 years of age.     

Immunohistochemical detection of tankyrase 2 in human breast tumors and normal renal tissue

Tankyrase, which functions at telomeres and other cellular compartments, is thought to be a positive regulator of telomerase; its isoenzyme tankyrase 2 has been cloned as a putative cancer antigen. This pilot immunohistochemical study was designed to examine whether tumors overexpress tankyrase 2. An antibody was generated by using synthetic peptide specific for tankyrase 2 and was tested by Western blot and immunocytochemically; no cross-reaction with isoenzyme 1 was revealed. Among tissue sections, two tumors of 18 specimens were positive for tankyrase 2. Others were negative or contained barely detectable protein. The surrounding normal tissues were negative. Tankyrase 2 was also revealed in epithelial cells of a limited number of normal renal tubules, whereas other renal tissues were negative. These data suggest that tankyrase 2 is not expressed ubiquitously in human tissues. To determine whether the up-regulation of tankyrase 2 is associated with tissue regeneration and cell proliferation, we compared the activity and concentration of the enzyme in a model human embryonic kidney cell line 293 arrested by serum deprivation and restimulated with serum. The serum-starved quiescent cell culture exhibited detectable protein as did the proliferating cells; enzyme activity dramatically increased in the latter. We conclude that pathologic overexpression of tankyrase 2 in some tumors may be a result of the cancer-related adaptation of the malignant cells dependent on tankyrase activity. Under normal conditions, the protein might be up-regulated during cell differentiation and also posttranslationally in proliferating cells. This study was supported by the Russian Foundation for Basic Research (grant no. 03-04-48835, principal investigator A.N. Kuimov)     

Frequent promoter hypermethylation and expression reduction of the glucocorticoid receptor gene in breast tumors

Previous studies have found that expression of the Glucocorticoid Receptor (GR) is altered or reduced in various cancers, while the GR promoter has been shown to be methylated in gastric, lung, and colorectal cancers. Examining a small cohort of matched normal and breast cancer samples we found that GR levels were dramatically reduced in almost all tumors in relation to their normal tissue. The methylation status of the GR promoter was assessed to determine if this observed decrease of expression in breast tumors could be due to epigenetic regulation. While it was not methylated in normal tissue, the GR proximal promoter was methylated in 15% of tumor samples, particularly, but not exclusively, in Estrogen Receptor positive tumors. GR expression in these tumors was particularly low and loss of GR expression was specifically correlated with methylation of the proximal promoter GR B region. Overall, these results show that hypermethylation of the promoter in tumors is a frequent event and suggests that GR may act as a tumor suppressor in breast tissue.     

Frequent promoter hypermethylation and expression reduction of the glucocorticoid receptor gene in breast tumors

Previous studies have found that expression of the Glucocorticoid Receptor (GR) is altered or reduced in various cancers, while the GR promoter has been shown to be methylated in gastric, lung, and colorectal cancers. Examining a small cohort of matched normal and breast cancer samples we found that GR levels were dramatically reduced in almost all tumors in relation to their normal tissue. The methylation status of the GR promoter was assessed to determine if this observed decrease of expression in breast tumors could be due to epigenetic regulation. While it was not methylated in normal tissue, the GR proximal promoter was methylated in 15% of tumor samples, particularly, but not exclusively, in Estrogen Receptor positive tumors. GR expression in these tumors was particularly low and loss of GR expression was specifically correlated with methylation of the proximal promoter GR B region. Overall, these results show that hypermethylation of the promoter in tumors is a frequent event and suggests that GR may act as a tumor suppressor in breast tissue.     

Imprint cytology of vacuum-assisted breast biopsy specimens: a rapid diagnostic tool in non-palpable solid lesions

Objective:  Imprint cytology provides a rapid preliminary diagnosis shortly after the completion of breast biopsy. This study aims to assess the validity of imprint cytology for the pre-operative diagnosis of non-palpable mammographic solid lesions excised by vacuum-assisted breast biopsy (VABB).
Methods:  Seventy-two women with non-palpable Breast Imaging Reporting and Data System 3 and 4 mammographic solid lesions without microcalcifications underwent VABB on the stereotactic Fischer's table with 11-G Mammotome vacuum probes. Imprint samples were examined (Diff-Quick stain, modified Papanicolaou stain and May-Grünwald–Giemsa). The cores were dipped into a CytoRich Red Collection fluid for a few seconds in order to obtain samples with the use of the specimen wash. After the completion of cytological procedures, the core was prepared for routine pathological study. The pathologist was blind to the preliminary cytological results. The cytological and pathological diagnoses were comparatively evaluated.
Results:  The sensitivity of the cytological imprints for cancer was 90%. The specificity of the method for cancer diagnosis was 100%. Two precursor lesions were present in the material: one case of atypical ductal hyperplasia, which was successfully detected, and one case of lobular neoplasia, which escaped detection. The cytological imprints were inadequate in four out of 72 cases (5.6%), but none of them were included within the malignant subgroup.
Conclusions:  Imprint cytology seems to be an important adjunctive tool in the management of patients with non-palpable mammographic solid lesions. Its very satisfactory sensitivity and optimal specificity could establish its use in general clinical practice.     

Association between estradiol, estrogen receptors, total lipids, triglycerides, and cholesterol in patients with benign and malignant breast tumors

This study addresses the correlation between the levels of estradiol (E₂), total lipids, triglycerides, and cholesterol in serum and tissue samples of age-matched patients with benign (40 cases; 16 were premenopausal and 24 were postmenopausal) and malignant (50 cases; 17 were premenopausal and 33 were postmenopausal) breast tumors. Estradiol levels were determined in serum and cytosol, estrogen receptors (ER) were assayed in cytosol, and total lipids, triglycerides and cholesterol were determined in serum and membrane fractions of all benign and malignant breast disease patients. Serum E₂ was significantly higher in malignant cases than benign ones (P<0.05) with a significant reduction (40%) in postmenopausal than premenopausal women. ER-positive tumors were significantly higher in postmenopausal women with malignant breast tumors than benign cases (P<0.05). Tissue levels of total lipids, triglycerides, and cholesterol were highly significantly increased in breast cancer women than women with benign breast diseases (P<0.05, P<0.005 and P<0.05 respectively) and they were also significantly correlated with estradiol levels. It could be concluded that the uptake of lipids from plasma by the tumor tissue is greatly correlated to estradiol and it may confirm the possible role of lipids as risk factor in breast cancer.     

Nutrients and nipple aspirate fluid composition: the breast microenvironment regulates protein expression and cancer aetiology

The aetiology of breast cancer is complex and multifactorial, and may include diet and xenobiotic compounds. A change in diet affects nutrient levels in blood, but to what extent diet can affect micronutrient concentrations in the breast is not yet well established. Breast nipple aspirate fluids (NAF) can be non-invasively obtained from the breast in most women; it represents a biological tool to assess metabolic changes in the breast ductal microenvironment. A wide variation in biomolecular and hormonal composition of NAFs collected from healthy and breast cancer patient may be due to genetic and nutritional factors; however, micro- and macro-nutrients may influence the secretory status of these women, thus NAF composition and risk of breast carcinoma. The aim of this overview is to highlight the detrimental/beneficial role that diet-related compounds in nipple aspirate fluid can have in breast cancer risk.     

Frequency of whole breast irradiation (WBRT) after intraoperative radiotherapy (IORT) is strongly influenced by institutional protocol qualification criteria

Background

Accelerated partial breast irradiation (APBI) is a promising method of adjuvant radiotherapy for select patients. Intraoperative radiotherapy (IORT) is a form of APBI, and appropriate patient selection is important.

Pure and mixed mucinous carcinoma of the breast: fine needle aspiration cytology findings and review of the literature

J. Cyrta, F. Andreiuolo, S. Azoulay, C. Balleyguier, C. Bourgier, C. Mazouni, M.‐C. Mathieu, S. Delaloge and P. Vielh
Pure and mixed mucinous carcinoma of the breast: fine needle aspiration cytology findings and review of the literature Objective: Mucinous (colloid) breast carcinoma accounts for 1–6% of all breast cancer. It comprises pure mucinous tumours and mixed infiltrating ductal carcinomas with a mucinous component. As this latter mixed form has a worse prognosis than pure colloid carcinoma, making this diagnosis on fine needle aspiration cytology (FNAC) might influence the choice of treatment. Methods: We report a consecutive series of 22 cases consisting of 17 mixed and five pure mucinous carcinomas diagnosed by cytology and verified on histopathology. Patients underwent FNAC at the one‐stop clinic of our institution during a 7‐year period of time. Cytological findings were evaluated by a semi‐quantitative method and included percentage of smear surface occupied by mucin, shape of cell groupings, size and outline of tumour nuclei as well as presence or absence of nucleolus. Results: Three of five pure mucinous carcinomas displayed at least two of the following features: abundant mucin, small nuclei and/or regular nuclear outlines. Sparse mucin, large nuclei, irregular nuclear outlines or the presence of nucleoli were found in 7 out of 17 mixed mucinous carcinomas but not in pure tumours. Conclusion: Cytopathological identification of patients with pure mucinous carcinomas may be performed in a limited number of cases.     

Flow cytometric analysis of human breast tumors and assessment of in vitro chemosensitivity by clonogenic assays

We report a double-agar clonogenic system adapted to human breast cancer. We optimized the conditions for cell growth and clonogenicity with respect to hormones (insulin, estradiol, progesterone) and components of the extracellular matrix (collagen, laminin and fibronectin). Using our experimental improvements, 67% of the breast tumor samples received were grown successfully. Tests on 21 tumors with three agents: Doxorubicin, Methotrexate and 5-Fluorouracil permit objective discrimination of the in vitro pharmacosensitivity of human breast tumors. Flow cytometric analysis reveal that 64% of the tumors were diploid and 36% were aneuploid. The aneuploid tumors grew better in the double agar layer system used for the clonogenic assay. The diploid tumors were especially rich in estrogen (ER⁺) and progesterone (PR⁺) receptors whereas the aneuploid tumors were mostly estrogen and progesterone receptors negative (ER^–/PR^–). Finally, we noted no difference in drug responsiveness depending on the tumor ploidy and steroid receptor content.Abbreviations DCC dextran coated charcoal - DI DNA index - DXB Doxorubicin - ECM extracellular matrix component - ER estrogen receptors - FCM flow cytometry - 5-FU 5-Fluorouracil - HTSCA human tumor stem cell assay - MTX Methotrexate - PBC primary breast carcinoma - PI proliferative index - PR progesterone receptors - SPF S phase fraction     

乳腺透明细胞癌:一种罕见的乳腺癌亚型

目的探讨乳腺透明细胞癌(glycogen-rich clear cell carcinoma of breast,GRCCC)的临床病理特征和诊断要点。方法报道1例GRCCC的临床病理、免疫组织化学结果及预后,并复习相关文献。结果患者,女性,44岁,2016年7月因发现右乳无痛性包块3年余,于外院行右乳改良切除术,病检提示乳腺癌,右乳癌术后化疗后6月余,发现全身多发骨转移,后来我院会诊。镜下显示乳腺浸润性癌,细胞排列成巢索状,间质为毛细血管,肿瘤细胞具有丰富透明的胞浆,呈多边形,边界清楚,核深染,核仁明显,肿瘤伴大片坏死,可见多处淋巴管及血管内癌栓。免疫组织化学染色显示肿瘤呈ER、PR和Her-2三重阴性,CK5/6局灶阳性,GATA-3阳性,P120细胞膜阳性,E-cadherin阳性,标记血管的CD34阳性,标记淋巴管的D2-40阳性,GCDFP-15阴性。会诊结果诊断为乳腺透明细胞癌。最初的局部治疗6个月后,病人出现多发骨和远处淋巴结转移。结论乳腺富糖原的透明细胞癌是乳腺癌一种罕见的组织学亚型,通常预后较差。     

Estrogen receptor β in the breast: role in estrogen responsiveness and development of breast cancer

Breast cancer is one of the most common forms of cancer observed in women. Endogenous estrogen is thought to play a major role in its development and estrogen receptor blockers are the most important drugs in its treatment. It has long been thought that any conditions or exposures, which enhance estrogenic responses, would result in an increased risk for breast cancer. The discovery of the second estrogen receptor, ERβ, which can have effects opposite to those of the well-known ‘original’ estrogen receptor (now called ER) challenges this simplistic view. In order to understand breast cancer one must first understand how the normal breast is maintained. The functions of ERβ in the breast remain to be defined but from what we have learnt about its activities in in vitro systems, this estrogen receptor may have a protective role in the breast. Studies in human and rodent breasts as well as in human breast cancer biopsies reveal that ERβ is by far the more abundant of the two ERs. Despite the role of estrogen in proliferation of the breast, neither of the two ERs appears to located in epithelial cells which divide in response to estrogen. In order to define the functions of ERβ in the normal and malignant breast, we have created mice in which the ERβ gene has been inactivated. Studies of the breasts of ERβ knock out mice (BERKO) revealed abnormal epithelial growth, overexpression of Ki67 and severe cystic breast disease as mice age.