Invasive Ductal Carcinoma - Research Paper Example

INVASIVE DUCTAL CARCINOMA [Pick the [Type the company pc Invasive Ductal Carcinoma (IDC) of the breasts are the most common and complicated forms of breast cancers affecting mostly older women. The disease arises from ducts spreads to adjacent breast tissue, appearing as a firm lump, painless with the skin appearing retracted. The causes of disease is still unknown but the origin can be traced back to piling of benign mutations leading to hyperplasia which in normal circumstances are suppressed by tumor suppressor genes. Prevention of the disease is not possible but early diagnosis and surgical removal along with radiotherapy and chemotherapy improve prognosis. Abstract 2 The Disease 3 The Breasts 5 Breast Development 6 Normal Physiology: 8 Pathophysiology 9 Histology of IDC 12 Molecular Biology of IDC 13 Signs & Symptoms 15 Treatment & Prognosis 16 Local Treatments 17 Systemic Treatments 19 REFERENCES 21 Abstract 2 The Disease 4 The Breasts 6 Breast Development 7 Normal Physiology: 9 Pathophysiology 10 Histology of IDC 13 Molecular Biology of IDC 14 Signs & Symptoms 16 Treatment & Prognosis 17 Local Treatments 19 Systemic Treatments 21 REFERENCES 23 INVASIVE DUCTAL CARCINOMA The Disease A century and a half ago Rudolf Virchow’s seminal ideas linked inflammation with cancer; and opened avenues for comprehension of the scariest disease mankind continues to face. Virchow suggested the presence of “lymphoreticular infiltrate”, at the site of inflammation was indicative of cancer initiation. The researches in previous decade have offered support to the ideas of Virchow; that malignant tissues formed during cancers create an inflammatory microenvironment (Balkwill & Mantovani, 2001). Breast cancers arise from the epidermal lining of the terminal duct lobular unit. Cancerous cells either remain confined to the terminal duct lobular unit and the draining duct; or proliferate beyond the basement membrane to the adjacent tissue. While the former is referred to as in situ or non-invasive; the latter is called invasive or infiltrating carcinomas. A misnomer used in the classification of invasive carcinomas was ductal and lobular carcinomas; where the two were believed to arise from ducts and lobules respectively. It is now understood that both of these types of breast cancer have origin in the lobule. The invasive breast cancers are now classified on the basis of specific cellular growth patterns and morphology of cells. Breast cancers with distinct features are called invasive cancers of special type; and the rest referred to as of no special type (figure 1) (Sainsbury et al., 2000). Cancers of breasts are the most common affecting women, with 232,340 new cases of invasive breast cancers reported from USA alone (ACS, 2014). Survival rates for breast cancer for women in the age range of 50-69 years, for five years is estimated to be 80%, for younger women it is slightly lower (Coleman et al., 2004). It is the second most common cause of death in women (first in case of Hispanic women) in USA (CDC, 2013). 72-80% of the cases of breast cancer are those of Invasive ductal carcinoma (IDC). The cancerous cells in IDC have the ability to metastasize as it invades the breast stroma and infiltrates in to the lympho-vascular spaces (Arps et al., 2013). This paper discusses the various aspects of IDC including pathophysiology, molecular biology, management and prognosis. Figure 1: Invasive Breast Cancer Classification (Sainsbury et al., 2000) The Breasts Figure 2: Anatomy of breast Breasts or mammary glands are modified sweat glands lying in the superficial fascia anterior to deep fascia of pectoral major. The understanding of human breast anatomy has grown little during the last century post the initial descriptions by Sir Astley Cooper. The organ comprises glandular tissue (46-83%) and adipose (16-51%) connected by fibrous connective tissue known as cooper’s ligaments. The adipose lies in parenchyma present in between the lobes while the cooper’s ligaments present perpendicular to superficial fascial layers support the lobes. The deeper layers of superficial fascia remain fused with the chest wall pectoral fascia. In between the inner layers of superficial fascia and pectoralis major fascia; and the chest walls at the posterior aspect of the breast lies the retromammary bursa that is involved in movement of breasts with respect to chest wall. Tissue distributions vary from women to women but remain same for an individual. 15-20 lobes exist that are formed of lobules containing alveoli which in turn contain lactocytes. The alveoli open in to small ducts that coalesce in to larger ducts which then merge to form the main milk duct. About to reach the areola the main duct widens in to a lactiferous sinus which narrows at nipple base and opens at the orifice on the surface. The adipose tissue usually does not occur within lobules but in between lobes (Ramsay et al., 2005). Most of the breast diseases originate in the network of glandular ducts and lobules, breast cancers specifically arise from the terminal ductal lobular unit (TDLU) (figure 6) (Hindle, 1999). Breast Development Human breasts are constantly developing organs, fully developed only after women experience pregnancy and childbirth, and hence can be understood by dividing the process into phases (Geddes, 2007). Fetal Phase: Six weeks in to gestation, breasts begin to develop from the ‘milk line’ or an ectodermal ridge present along the anterior body wall in between groin and axilla. A series of events follow thereafter (Figure 3). Figure 3: Fetal stages of breast development After birth, infants’ breasts have been known to express colostrums due to pro-lactation hormones present in fetal circulation. After 4 weeks of birth, breasts regress with simultaneous decline in prolactin secretion from anterior pituitary gland of child. Pre-Puberty phase: Isometric growth of breast Puberty Phase: Onset of puberty is characterized by allometric growth of stroma and epithelium, followed by increase in breast size due to deposition of adipose. Simultaneously an extensive network of ducts develops as a consequence of ductal elongation and branching; along with formation of terminal duct lobular units. The breast development during puberty is regulated by hormones such as oestrogen, prolactin, luteinizing hormone, follicle stimulating hormone, and growth hormone. Menstrual Cycle Changes: Breasts undergo multiple changes at different stages (figure 4). Changes during Pregnancy: First half of pregnancy is marked by extensive branching and elongation of ducts with intense mammogenesis. The growth occurs as a consequence of many hormones such as oestrogen, progesterone, prolactin, growth hormone, epidermal growth factor, fibroblast growth factor, insulin-like growth factor, and parathyroid hormone–related protein. By the middle of pregnancy, colostrums appears in alveoli as a consequence of secretory development. The final stages of pregnancy are marked by further increase in size of lobules. Mammry blood flow rises along with high metabolic activity and increased temperature. With advancing age, there is decrease in mitosis, reaching a plateau at around the age of 35 when a plateau is reached. Figure 4: Breast changes during Menstrual Cycle Normal Physiology: The functional activity of breasts begins only at the lactation phase, under the influence of prolactin produced by the anterior pituitary. It binds to mammary epithelial secretory cells stimulating synthesis of mRNA responsible for milk protein synthesis. Prolactin secretion in turn is caused by infant suckling. At this stage, many changes occur such as darkening of areola, increase in size of Montgomery glands, the secretions from which protect mother from pathogens as well as stress during breast-feeding (Geddes, 2007). Aqueous components of milk are synthesized by the exocytotic pathway, proteins being synthesized by ribosomes and modified by Golgi body. Golgi vesicles also synthesize lactose from UDP-galactose and glucose, which is osmotically transferred out of the vesicles. Thus milk secretion involves five distinct processes occurring simultaneously in mammary epithelium (figure 5) (Neville, 1998): I. Exocytosis II. Lipid synthesis & secretion III. Transmembrane secretion of ion and water IV. Trancytosis of extraalveolar proteins such as immunoglobulins, hormones and albumin V. Paracellular Pathway: direct transfer between milk space and interstitial space. This pathway remains inactive (blocked by zonula occludens) during lactation thereby blocking the flow between milk glands and interstial spaces. Figure 5: Alveolar Cell of lactating mammary gland (N, nucleus; TJ, tight junction; GJ, gap junction; D, desmosome; SV, secretory vesicle; FDA, fat-depleted adipocyte; PC, Plasma Cell; BM, basement membrane; ME, cross section through process of myoepithelial cell; RER, rough endoplasmic reticulum) Milk ejection from breasts requires stimulation of nipples. This is accomplished by nerve impulses to hypothalamus that stimulate posterior pituitary glands to secrete oxytocin in the blood. Oxytocin is responsible for the contraction of myoepithelial cells around the alveoli, ejecting milk in to the duct (Geddes, 2007). Pathophysiology IDC arise from cells of the breast duct epithelial lining. IDC is characterized by lack of any of the macroscopic features specific to any of the special types of breast cancers. Epithelial lesions arising from the TDLU are malignant, unilateral and usually occur in the outer upper quadrant, though not exclusively in this area. The tissues in IDC are irregular and are seen adhering to skin or muscle in mammography or ultrasound. They acquire stellate or speculated appearances as a consequence of protrusions of malignant glandular growth projecting in to the tissue surrounding the tumor. They exhibit firmness resulting from desmoplastic reactions which occur in response to the tumor cells. Stromal response leads to accumulation of collagen and fibroblasts that further contributes to irregularity of the tumor mass. In certain cases of IDC, stromal response is absent hence the firmness level may be lesser. Gray white lesions with yellow streaks are observed with necrotic regions and hemorrhage being common characteristics (Jarasch et al., 1998). Figure 6: Glandular Ducts and lobules (Hindle, 1999) It has been postulated that IDC development involves a sequence of step beginning with premalignant hyperplastic lesion accompanied by atypia or lacking it; followed by ductal carcinoma in situ (DCIS) and finally invasive form of cancer. This progression can be either very slow or can occur really fast (Castro et al., 2008). The disease progression has however been found to be non-obligatory and influenced by a multitude of factors including random genetic mutations, epigenetic factors and influence of adjacent stromal cells. Of these factors genetic mutations in epithelia of tumor cells are of most significance in carcinoma progression as well as invasion (Wellings & Jensen, 1973). Histologically breast epithelium is host to numerous growth abnormalities at the molecular level, most of which are not manifested physically or physiologically; though some of these may be risk factors rendering the cells vulnerable to malignant alterations or are precursors of the same (Wellings & Jensen, 1973). The malignant process has been described as piling up of genetic abnormalities that enable the cell to overpower the normal cell division and growth process and breakdown the stringent environmental control. Specific pathway analysis has lead to identification of 11 genes of the 145 involved in THFβR pathway to be involved in carcinogenesis. At least one of these RBL1 has been found to cause tumor suppression (Amrutti et al., 2013). The progress of DCIS to IDC is not well understood but several probable genes have been identified such as LOX and SULF-1 that may impart the ability to cancer cells to invade the adjacent tissues. These two genes can be considered as molecular markers to predict progression of DCIS to more malignant IDC. AIK1 (centrosomal serine/threonine kinase has also been shown to be overexpressed in IDCwith mild levels of the gene expression has been reported from benign lesions (Castro et al., 2008). The earliest histologically significant but usually benign lesions capable of progression to breast cancer include CCH (columnar cell hyperplasia), ADH (Atyical ductal hyperplasia), DCIS. CCH involves lobular expansion as a consequence of hyperplasia of columnar epithelial cells and exhibit differing levels of atypia and cytological stratification. The lesions of CCH are representative of abnormality in terms of bilateral and multifocal growth up to 100 times the size and number of cells compared to normal TDLU. The reasons for this progression are not yet understood but estrogen and estrogen receptors are speculated to be involved in the process (Lee et al., 2005). ADH is a rare abnormality manifested in epithelial cells arising without any known reasons. The epithelial cells lying in or around the CCH, are involved in ADH and have the ability to detach from the basement membrane to accumulate in cribriform arrangements causing slight distension of the ducts and acini wherein they reside. ADH cells are characterized by occurrence of multiple allelic imbalances that are characteristic of breast cancer cells and also represent the leap from polyclonal cells of CCH to monoclonal (Wellings & Jensen, 1973). Under normal circumstances these benign lesions are suppressed by several genes that have yet to be identified. Some probable candidates are RBL1 (Amrutti et al., 2013), CSTA (protease inhibitor), and certain genes involved in cell signaling and adhesion such as FAT1, DST, TMEM45A (Lee et al., 2012). A simultaneous event occurring is angiogenesis or the growth and restructuring of blood vessels. Tumor angiogenesis is a critical factor determining tumor progression, metastasis and invasion. Though significant differences in breast history and tumor size in patients of these three types of carcinomas is lacking; old age and menopause are found to be important risk factors for IDC. IDC manifests a higher degree of malignancy compared to rest two (Wei et al., 2012). Histology of IDC Histological features of IDC vary with individual cases with tumor cells growing as isolated cells in small clusters, in sheets that remain diffused or in form of nests, trabeculae or glands. The shape of tumor mass depends on the stromal reaction and glandular growth. Varied tubule or gland differentiation is observed ranging from being completely undifferentiated to being localized or extensive. Individual tumor cells are usually larger than normal epithelial cells and exhibit high nuclear pleomorphism. They are with more cytoplasm and are eosinophilic. Necrotic regions can easily be seen. In certain cases few tumor cells are seen dispersed in an abundance of dense stroma while in others tumor lacks a stromal response penetrating in to breast parenchymal cells. The degree of mitosis also varies from negligible to profuse. In approximately 50% of the cases calcification has been reported that is either granular; fine or course; or psammoma type in rare cases (Jarasch et al., 1998). Figure 7: Invasive Ductal Carcinoma Molecular Biology of IDC The significance of stromal interactions with cells of epithelium in the process of embryonic development and tumor formation has been proved. The processes of organogenesis, cancer development, inflammation, repair and fibrosis involve the common element myofibroblasts that make a significant contribution to these processes by secreting chemokines, growth factors, cytokines, inflammatory agent and matrix proteins as well as proteases (Dabiri et al., 2013). In IDC the stroma is formed by fibroblasts and myofibroblasts (Jarasch et al., 1998). Rather than mutations in epithelial and stromal cells, it has been suggested that cancers result as a consequence of altered stromal epithelial cell components’ interactions. Reversible alterations are induced in the phenotype of tumor cells that enables it to metastasize and proliferate. Myofibroblasts are the main cells of stroma that are considered to be actively involved in the development of reactive stroma, which themselves are induced to proliferate as reactive myofibroblasts by cancer cells (Dabiri et al., 2013). Myofibroblasts produce collagen I and II, versican, fibronectin isoforms, tenascin and proteases. The changes in the extracellular matrix which are responsible for cancer development and proliferation are induced by metalloproteinases, urokinase plasminogen activator, and fribroblast activating factor. Myofibroblasts also secrete potential angiogenic factors such as connecting tissue growth factors, and transforming growth factor beta-1. Certain stromal genes are suppressed during the development of breast carcinoma for e.g. CD34 while others such as those indicative of myofibroblastic differentiation are activated e.g. smooth muscle actin (SMA) gene. SMA reactive myofibroblasts have been reported to accumulate at specific points in invasive carcinomas, though not exclusively so. Moreover the accumulation levels exhibit a positive correlation with grades of carcinoma (Dabiri et al., 2013). Proinflammatory cytokines, growth factors and tumor promoters activate Cyclooxygenase 2 (COX-2) which is the inducible isoform of prostaglandin H synthase. It has been held accountable in multiple human carcinomas and affects cell proliferation, division, adhesion, apoptosis, angiogenesis and immune response.. Its mechanism of action needs further elucidation. Another protein implicated in breast cancer is HER-2 (Human Epidermal growth Factor receptor type 2). It leads to proliferation stimulation and its overexpression has been found to be due to c-erb-b2 gene activation. Once it forms heterodimers with other HER family receptors such as HER-3, during overexpression its role in carcinogenesis become more significant. It leads to hyperactivity of cell signaling pathways that result in cell proliferation and tumor formation beyond control. HER-2 has also been reported to exercise control on the expression and coexpress with COX-2 in IDC (Lucarelli et al., 2011). Another contributing factor identified for the progress of breast carcinoma is sex hormones estrogen and progesterone; since breasts are sex hormone dependent organs. The sex hormones play a significant role in growth, cell proliferation, and development through the cellular binding of receptors for the two hormones. Of these two receptors, estrogen receptor (ER) plays an important role in breast cancer while ER along with progesterone receptors (PR) bears close relation with prognosis and endocrine therapy (Wei et al., 2012). Two thirds of IDC cases have been reported to express ER and hormonal therapy has been resorted to manage intumoral estrogen actions. ER is involved in ligand dependent transcription induction of many genes, and the expression profiles of these genes have been correlated with molecular functions of estrogen such as cell division, anti-apoptosis, metastasis, invasion, resistance to hormonal therapy in IDC (Ebata et al., 2012). Signs & Symptoms Distinguishing factor of IDC compared to DCIS is presence of stromal invasion. Signs and symptoms of breast cancer are identifiable only when they become invasive in which case prognosis is difficult. The major signs and symptoms are (Say & Donegan, 1974): 1. Painless breast mass that is firm and growing gradually. 2. Alterations in breast contour 3. Alterations in nipple discharge that can be bloody. 4. Axillary or supraclavicular adenopathy 5. Thickening of skin or ulceration 6. Lesion appearance and consistency vary depending on its composition 7. Cystic areas are usually uncommon but if present may be attributed to necrosis and occur with hemorrhage. Non-cystic necrotic areas may be chalky or hemorrhagic. Figure 8: Advanced IDC Treatment & Prognosis Prevention is not possible for cancer but early detection improves prognosis. Ten year survival rates for patients with lesions less than 2cms are better than 90%compared to larger lesions that have higher probability of having metastasized. Ultrasound techniques and mammography help clearly differentiate IDC due to a large tumor mass, with indtraductal carcinoma, type of calcification and irregular invasiveness (Wei et al., 2012). Cancer management and prognosis are determined by disease pathological factors including tumour size and grade, histological type, ER and PR status, HER2 expression etc. Hence once diagnosed the primary step to treatment of IDC is its staging. Staging enables the extent of damage and hence facilitates the decision regarding management and prognosis. The tumor Node Metastases (TNM) System of staging (figure 9) has been replaced by the Union Against Cancer (UICC) system (figure 10) which incorporates and develops on TNM system. Figure 9 (Sainsbury et al., 2000) Figure 10 (Sainsbury et al., 2000) Individuals diagnosed with IDC need to undergo full blood count, liver function tests and chest radiography to ensure presence of gross evidence of IDC. Stage I and II patients need not undergo further investigations but those with higher grading are provided liver and bone scans to decide further management (Sainsbury et al., 2000). Treatments available for IDC include local treatments such as surgery and radiotherapy; and systemic treatments including chemotherapy, hormonal therapy and Biological therapy. The systemic treatments focus on management of cancer cells that have infiltrated other tissue or are recommended for control of recurrence after local treatments; in which case it is known as adjuvant therapy (Breastcancer.org) Local Treatments Patients of IDC grades III and above usually are recommended localized treatments such as surgery and radiotherapy along with systemic treatments to control both local as well as micrometastatic disease spread. Surgery is either breast conservation comprising of removal of timorous tissue along with adjacent normal tissues or could be mastectomy. Mortality and recurrence rates for both forms of surgery have been found comparable. Selection of either of these is based on clinical and pathological criteria such as incomplete initial excision, age of patient, extensive in situ spread, histological grade and lymphatic or vascular infiltration of the carcinoma. Figure 11 (Sainsbury et al., 2000) The size limitation in breast conservation surgery is exclusively due to cosmetic factors, wherein it leads to poor results. Figure 12 (Sainsbury et al., 2000) Mastectomy involves certain complications such as flap necrosis, seroma and infection. Post breast conservation surgery, follow ups are scheduled once a year for clinical examination, and once or twice a year for mammography. After mastectomy annual clinical examinations are scheduled for five years; and annual or biannual mammography are conducted indefinitely. Radiotherapy involving doses of 40-50Gy over a period of 3-5 weeks needs to be administered to all patients post wide local excision. Post mastectomy radiotherapy should be administered only in cases that involve high local recurrence risk. Complications associated with radiotherapy have enabled minimized administration of doses and hence reduced risks considerably. Radiation pneumonitis and rib damage incidences have reduced considerably, and so are incidences of skin reaction followed by skin telangiectasia (Sainsbury et al., 2000). Grade III and above IDC have reported to show poor prognosis. Recurrent carcinomas due to original primary tumor or a new primary tumor are frequent, and follow ups are essential. Recurrence in residual breast tissue has better prognosis than a local occurrence in mastectomy scar since the latter indicates systemic metastases. The former is treated by local excision along with radiotherapy &/or systemic chemotherapy depending on the size and level of infiltration of carcinoma. Fulford and colleagues (2007) report the presence of a distinct group of Grade III IDC of breast that exhibit poorer prognosis addressing them as ‘bad’ carcinoma or basal like grade III IDC compared to rest ‘good’ carcinomas. The two types differ in metastasis patterns. The basal like grade III IDC have a good long term survival rate but exhibit poor survival rates after metastases. Systemic Treatments Chemotherapy involves oral administration or venous injection of drugs. IDC with tumors larger than 1cm diameter and infiltrated in to lymph nodes are recommended for chemotherapy. The common combinations of drugs recommended in IDC, and their activity are listed in table 1 and 2 respectively. Table 1: Drug combinations recommended for breast carcinoma (National Cancer Institue) Drug Combination Component Drugs AC Doxorubicin Hydrochloride (Adriamycin), Cyclophosphamide AC-T Doxorubicin Hydrochloride (Adriamycin), Cyclophosphamide, Paclitaxel (Taxol) CAF Cyclophosphamide, Doxorubicin Hydrochloride (Adriamycin), Fluorouracil CMF Cyclophosphamide, Methotrexate, Fluorouracil FEC Fluorouracil, Epirubicin hydrochloride, Cyclohosphamide TAC Docetaxel (Taxotere), Doxorubicin Hydrochloride (Adriamycin), Cyclophosphamide Table 2: Drugs & Mechanism of Action (ACS, 2014) Drugs Mechanism of action Doxorubicin Anthracycline Antibiotics, DNA damage by intercalation of the anthracycline portion, metal ion chelation, or by generation of free radicals. Cytotoxicity non specific in terms of phase of cell cycle Cyclophosphamide Alkylating agents, blocks DNA formation, prevents cell division, causes cell death Taxol Prevets spindle assembly, prevents metaphase/anaphase checkpoint crossing Fluorouracil Anti metabolite , prevents DNA RNA formation Methotrexate Anti metabolite, prevents DNA RNA formation Epirubicin hydrochloride Anthracycline Antibiotics Another form of systemic therapy is hormone therapy. It is used in cases of IDC that are hormone receptor positive specifically those that express estrogen or progesterone. The treatment involves administration of selective estrogen receptor modulators (SERM) which prevent the impact of estrogen on estrogen receptor thereby preventing breast growth. Tamoxifen is the common drug used for estrogen responsive breast carcinomas. 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