THe Breast «© o NORMAL STRUCTURE, BREASTTUMOURS CARCINOMA OF THE BREAST INEGAMMATIONS FIBROADENOMA NON-INVASIVE (IN SITU) FIBROCYSTIC CHANGE PHYLLODES TUMOUR CARCINOMA GYNAECOMASTIA (CYSTOSARCOMA INVASIVE CARCINOMA (BYPERTROPHY OF PHYLLODES) PAGET'S DISEASE OF THE NIPPLE SMALE BREAST) INTRADUCTAL PAPILLOMA GRADING, STAGING AND PROGNOSIS: NORMAL STRUCTURE STROMAL COMPONENT. The supportive stroma of ‘The breast is a modified skin appendage which is func tional in the females during lactation but is rudimentary in the males. Microanatomy of the breast reveals 2 types of tissue components: epithelial and stromal (Fig, 23.1). Ina fully-developed non-lactating female breast, the epithelial component comprises less than 10% of the total volume but is more significant pathologically since majority of lesions pertain to this portion of the breast. EPITHELIAL COMPONENT. The epithelial component of the breast consists of the breast lobules and the collec- ting duct system. The breast is divided into about 20 lobes. Each lobe consists of breast lobules which drain their secretions through its collecting duct system and opens into the nipple through its own main excretory duct, lactferous duct, The segment of lactiferous duct subjacent to the nipple shows a small dilatation called lactiferous sinus. Each lactiferous duct has its own collec- ting duct system which has branches of smaller diameter, ultimately terminating peripherally as terminal ducts in the breast lobules which are the main secretory functional units of the mammary tissue during lactation. The breast lobules are composed of acini or ductules which are lined by cuboidal epithelium during resting mammary gland but develop secretory vacuoles in the last trimester of pregnancy. The terminal ducts too are lined by a single layer of cuboidal epithelium; relatively larger ducts have double-layered epithelial lining which becomes pseudostratified in the major ducts. The main lactiferous ducts are lined by stratified squamous epithe- lium. In addition to the epithelial cells, the intermediate collecting ducts are supported by myoepithelial cells. the breast consists of variable amount of loose connec tive tissue and adipose tissue during different stages of reproductive life. The stromal tissue of the breast is present at 2 locations: intralobular and interlobular stroma. Intralobular stroma encloses each lobule, and its acini and ducts, and is chiefly made of loose connective tissue, myxomatous stroma and a few scattered lympho~ cytes. Interlobular stroma separates one lobule from the other and is composed mainly of adipose tissue and some loose connective tissue ‘The most important disease of the breast is cancer However, there are a few inflammatory lesions, benign tumours and tumour-like lesions which may be con fused clinically with breast cancer. These pathologie lesions are described first, followed by an account of carcinoma of the breast. INFLAMMATIONS Inflammation of the breast is called mastitis. Impo1 types of mastitis are acute mastitis and breast absc chronic mastitis, mammary duct ectasia (oF plasma mastitis), traumatic fat necrosis and galactocele. st Abscess Acute Mastitis and Br ‘Acute pyogenic infection of the breast occurs cl during the first few weeks of lactation and someti by eczema of the nipples. Bacteria such as staphyl and streptococci gain entry into the breast by devel ment of cracks and fissures in the nipple. Initially localised area of acute inflammation is produced whi if not effectively treated, may cause single or multiHE Breast ig fea im Duetules or acini Terminal duct Collecting duct ‘Adipose tissue Lobe Lobule Leactiferous duct Lactiferous sinus Nipple LESIONS ‘Adenoma nipple Intraductal papilloma: Fat necrosis Hyperplasias, carcinomas, Fibroadenoma, cysts Microanatomy of the breast and major lesions at various sites. breast abscesses. Extensive necrosis and replacement by fibrous scarring of the breast with retraction of the nipple may result. Granulomatous Mastitis Although chronic non-specific mastitis is uncommon, chronic granulomatous inflammation in the breast may occur as a result of the following 1. Systemic granulomatous disease e.g. as part of systemic sarcoidosis, Wegener's granulomatosis. 2. Infections e.g. tuberculosis which is not so uncommon in developing countries like India and may be mis- diagnosed clinically as breast cancer owing to axillary nodal involvement. Tubercle bacilli reach the breast by haematogenous, lymphatic or direct spread, usually from the lungs or pleura. Pathologically, typical caseat- ing tubercles with discharging sinuses through the surface of the breast are found. ZN staining may demonstrate acid-fast bacilli. Fungal infection of the breast may occur in immunocompromised patients. 3. Silicone breast implants implanted on either breast cancer patients after mastectomy or as breast augmen- tation cosmetic surgery may rupture or silicone may slowly leak into surrounding breast tissue. This incites chronic inflammatory reaction of lymphocytes, macro- phages and foreign body giant cells. Eventually, a surrounding fibrous capsule forms and after long period it may even be calcified. 4, Idiopathic granulomatous mastitis is an uncommon form of reaction around lobules and ducts in the absence of any known etiology. Exact pathogenesis is not known but probably it is a form of hypersensitivity reaction to luminal secretion of the breast epithelium during lactation. Mammary Duct Ectasia (Plasma Cell Mastitis) Mammary duct ectasia is a condition in which one or more of the larger ducts of the breast are dilated and filled with inspissated secretions. These are associated with periductal and interstitial chronic inflammatory changes. Duct ectasia affects women in their 4th to 7th decades of life. The patients may remain asymptomatic or there may be nipple discharge, retraction of the nipple due to fibrous scarring and clinically palpable dilated ducts in the subareolar area. The lesion may be mistaken for carcinoma of the breast. The etiology of the condition remains unknown but it appears to begin with periductal inflammation followed by destruction of the elastic tissue to cause ectasia and periductal fibrosis. PATHOLOGIC CHANGES. Grossly, the condition appears as a single, poorly-defined indurated area in the breast with ropiness on the surface. Cut section shows dilated ducts containing cheesy inspissated secretions. Histologically, the features are as under: 1. Dilated ducts with either necrotic or atrophic lining by flattened epithelium and lumen containing granular, amorphous, pink debris and foam cells. 2. Periductal and interstitial chronic inflammation, chiefly lymphocytes, histiocytes with multinucleate histiocytic giant cells. Sometimes, plasma cells are present in impressive numbers and the condition is then termed plasma cell mastitis. 3. Occasionally, there may be obliteration of the ducts by fibrous tissue and varying amount of inflam- mation and is termed obliterative mastitis. Fat Necrosis Focal fat necrosis of an obese and pendulous breast followed by an inflammatory reaction is generally initia- ted by trauma, The condition presents as a well defined mass with indurated appearance.Grossly, the excised lump has central pale cys of necrosis Histologically, there is disruption of the regular pattern of lipocytes with formation of lipid-filled spaces surrounded by neutrophils, lymphocytes, plasma cells and histiocytes having foamy cytoplasm and frequent foreign body giant cell formation. In late stage, there is replacement fibrosis and even calcification. Galactocele A galactocele i occurring during lactation. The mammary duct is obstructed and dilated to form a thin-walled cyst filled with milky fluid. Rarely, the wall of galactocele may get secondarily infected. FIBROCYSTIC CHANGE The term fibrocystic change of the female breast is a histologic entity characterised by’ i) cystic dilatation of terminal ducts; ii) relative increase in inter- and intralobular fibrous tissue; and iii) variable degree of epithelial proliferation in the terminal ducts. It was previously termed fibrocystic disease but is currently considered as an exaggerated physiologic phenomena and not a disease, or was called as benign mantmary dysplasia under the mistaken belief that all forms are dysplastic or precancerous condition, and hence has attracted considerable interest. It is the most common benign breast condition producing vague ‘lumpy’ breast rather than palpable lump in the breast of adult women, Its incidence has been reported to range from 10-20% in adult women. Most of the patients with fibrocystic change are between 3rd and 5th decades of life, with dramatic decline ints incidence after menopause suggesting the role of oestrogen in its pathogenesis. It is important to identify the spectrum of histology or cytology findings by FNAC in fibrocystic changes since only some subset of changes have an increased risk of development of breast cancer. Presently, the spectrum of histologic changes are divided into two clinicopathologically relevant groups: ‘A. Nonproliferative changes (or cyst formation and fibrosis, or simple fibrocystic change); B. Proliferative changes (includes epithelial hyperplasia and sclerosing adenosis). A. Nonproliferative Fibrocystic Changes (Cyst Formation and Fibrosis, ‘Simple Fibrocystic Change) Formation of cysts of varying size and increase in fib- rous stroma are the most common features of fibrocystic disease. Cysts are formed by dilatation of obstructed collecting ducts, obstruction being caused by periductal fibrosis following inflammation or fibrous overgrowth from oestrogen stimulation. PATHOLOGIC CHANGES. Grossly, the cysts are rarely solitary but are usually multifocal and bilateral. They vary from microcysts to 5-6 cm in diameter. The usual large cyst is rounded, translucent with bluish colour prior to opening (blue-dome cyst). On. opening, the cyst contains thin serous to haemor- rhagic fluid. Microscopically, the features of simple fibrocystic change are as under (Fig. 23.2) (COLOUR PLATE XXXxi: cL im: 1. The cyst lining shows a variety of appearances. Often, the epithelium is flattened or atrophic. Frequently, there is apocrine change or apocrine meta- plasia in the lining of the cyst resembling the cells of apocrine sweat glands. Occasionally, there is simul- taneous epithelial hyperplasia (discussed below) forming tiny intracystic papillary projections of piled up epithelium. Hyperplastic Adenosis epithelium Increased Apocrine metaplasia fibrous stroma | Dilated ducts ‘Simple fibrocystic change showing cystic dilatation of ducts: increase in fibrous stroma. There is mild epithelial hyperplasia terminal duets.2. There is increased fibrous stroma surrounding the cysts and variable degree of stromal lymphocytic infiltrate, B. Proliferative Fibrocystic Changes (Epithelial Hyperplasia and Sclerosing Adenosis) EPITHELIAL HYPERPLASIA. Epithelial hyperplasia (or epitheliosis in the British literature) is defined as increase in the layers of epithelial cells over the basement membrane to three or more layers in the ducts (ductal Iyperplasia) or lobules (lobular hyperplasia). The latter condition, lobular hyperplasia, must be distinguished from adenosis (discussed separately) in which there is increase in the number of ductules or acini without any change in the number or type of cells lining them. Epithelial hyperplasia may be totally benign or may have atypical features. It is the latter type of hyperplasia which is precancerous and is associated with increased risk of developing breast cancer. Microscopically, epithelial hyperplasia is charac- terised by epithelial proliferation to more than its normal double layer. In general, ductal hyperplasia is termed as epithelial hyperplasia of usual type and may show various grades of epithelial proliferations, while lobular hyperplasia involving the ductules or acini is always atypical. 1. Mild hyperplasia of ductal epithelium consists of at least three layers of cells above the basement membrane, present focally or evenly throughout the duct (Fig. 23.2). 2. Moderate and florid hyperplasia of ductal type is associated with tendency to fill the ductal lumen with proliferated epithelium. Such epithelial prolife- rations into the lumina of ducts may be focal, forming papillary epithelial projections called ductal papillo- ‘matosis, or may be more extensive, termed florid apillomatosis, or may fill the ductal lumen leaving, only small fenestrations in it. 3. Of all the ductal hyperplasias, atypical ductal hyperplasia is more ominous and has to be distingui- shed from intraductal carcinoma (page 787). The proliferated epithelial cells in the atypical ductal hyperplasia partially fill the duct lumen and produce irregular microglandular spaces or cribriform pattern, The individual cells are uniform in shape but show loss of polarity with indistinct cytoplasmic margin and slightly elongated nuclei 4. Atypical lobular hyperplasia is closely related to lobular carcinoma in situ (page 788) but differs from the latter in having cytologically atypical cells only in half of the ductules or acini. Chapter 23: The Breast Bas) SCLEROSING ADENOSIS. Sclerosing adenosis is benign proliferation of small ductules or acini and intralobular fibrosis. The lesion may be present as diffusely scattered microscopic foci in the breast parenchyma, or may form an isolated palpable mass which may simulate an infiltrating carcinoma, both clinically and pathologically. Grossly, the lesion may be coexistent with other components of fibrocystic disease, or may form an isolated mass which has hard cartilage-like consistency, resembling an infiltrating carcinoma. Microscopically, there is proliferation of ductules or acini and fibrous stromal overgrowth. The histologic appearance may superficially resemble infiltrating carcinoma but differs from the latter in having maintained lobular pattern and lack of infiltration into the surrounding fat. Prognostic Significance Since there is a variable degree of involvement of epithelial and mesenchymal elements in fibrocystic change, following prognostic derivations can be made: 1. Nonproliferative fibrocystic changes of fibrosis and cyst formation donot carry any increased risk of developing invasive breast cancer. 2. Identification of general proliferative fibrocystic changes are associated with 1.5 to 2 times increased risk for development of invasive breast cancer. 3, Multifocal and bilateral proliferative changes in the breast pose increased risk to both the breasts equally. 4. Within the group of proliferative fibrocystic changes, atypical hyperplasia, in partilcular, carries 4 to 5 times increased risk to develop invasive breast cancer later. This risk is further more if there is a history of breast cancer in the family. GYNAECOMASTIA (HYPERTROPHY OF MALE BREAST) Unilateral or bilateral enlargement of the male breast is known as gynaecomastia. Since the male breast does not contain secretory lobules, the enlargement is mainly due to proliferation of ducts and increased periductal stroma. Gynaecomastia occurs in response to hormonal stimulation, mainly oestrogen. Such excessive oestro- genic activity in males is seen in young boys between 13 and 17 years of age (pubertal gynaecomastia), in men over 50 years (senescent gynaecomastia), in endocrine diseases associated with increased oestrogenic or decrea- sed androgenic activity e.g. in hepatic cirrhosis, testicular tumours, pituitary tumours, carcinoma of the lung,[El Sica Prooer exogenous oestrogen therapy as in carcinoma of the prostate and testicular atrophy in Klinefelter’s syndrome (secondary gynaecomastia); and lastly, enlargement without any obvious cause (idiopathic gynaecomastia). PATHOLOGIC CHANGES. Grossly, one or both the male breasts are enlarged having smooth glistening white tissue. Microscopically, there are 2 main features: 1. Proliferation of branching ducts which display epithelial hyperplasia with formation of papillary projections at places. 2. Increased fibrous stroma with, myxoid appear- ance. BREAST TUMOURS ‘Tumours of the female breast are common and clinically significant but are rare in men. Among the important benign breast tumours are fibroadenoma, phyllodes tumour (cystosarcoma phyllodes) and intraductal papilloma. Carcinoma of the breast is an important malignant tumour which occurs as non-invasive (carci- noma’ in situ) and invasive cancer with its various morphologic varieties. FIBROADENOMA Fibroadenoma or adenofibroma is a benign tumour of fibrous and epithelial elements. It is the most common benign tumour of the female breast. Though it can occur at any age during reproductive life, most patients are between 15 to 30 years of age. Clinically, fibroadenoma Gollagenic stroma Compressed duct a Fibroadenoma of the breast, microscopic patterns. generally appears as a solitary, discrete, freely mobile hodule within the breast. Rarely, fibroadenoma may contain in situ or invasive lobular or ductal carcinoma, for the carcinoma may invade the fibroadenoma from the adjacent primary breast cancer. PATHOLOGIC CHANGES. Grossly, typical fibro- adenoma is a small (2-4 cm diameter), solitary, well- encapsulated, spherical or discoid mass. The cut sur- face is firm, grey-white, slightly myxoid and may show slit-like spaces formed by compressed ducts. Occasionally, multiple fibroadenomas may form part of fibrocystic disease and is termed fibroadenomatosis. . Less commonly, a fibroadenoma may be fairly large in size, upto 15 cm in diameter, and is called giant fibroadenoma but lacks the histologic features of cysto- ‘sarcoma phyllodes (see below). Microscopically, fibrous tissue comprises most of a fibroadenoma. The arrangements between fibrous overgrowth and ducts may produce two types of patterns which may coexist in the same tumour. These ‘re intracanalicular and pericanalicular patterns (Fig. 23.3): 1 Intracanalicular pattern is one in which the stroma compresses the ducts so that they are reduced. to slit-like clefts lined by ductal epithelium or may appear as cords of epithelial elements surrounding masses of fibrous stroma (COLOUR PLATE XXXk: CL 123). lm Pericanalicular pattern is characterised by encir~ cling masses of fibrous stroma around the patent or dilated ducts. Collagenic stroma J SF LANE The fibrous stroma may be quite cellular, or there may be areas of hyalinised collagen. Sometimes, the stroma is loose and myxomatous. Occasionally, the fibrous tissue element in the tumour is scanty, and the tumour is instead predominantly composed of closely-packed ductular or acinar proliferation and is termed fubular adenoma. If such an adenoma is composed of acini with secretory activity, itis called lactating adenoma seen during pregnancy or lactation. Juvenile fibrondenoma is an uncommon variant of fibro- adenoma which is larger and rapidly growing mass seen in adolescent girls but fortunately does not recur after excision. PHYLLODES TUMOUR (CYSTOSARCOMA PHYLLODES) Cystosarcoma phyllodes was the nomenclature given by Miller in 1838 to an uncommon bulky breast tumour with leaf-like gross appearance (pltyllodes=leaf-like) having an aggressive clinical behaviour. Most patients are between 30 to 70 years of age. Grossly, the tumour resembles a giant fibroadenoma but is distinguished histologically from the latter by more cellular connective tissue, The WHO classification of breast tumours has proposed the term ‘phyllodes tumour’ in place of misleading term of ‘cystosarcoma phyllodes’. Phyllodes tumour can be classified into benign, borderline and malignant on the basis of histologic features. Local recurrences are much more frequent than metastases PATHOLOGIC CHANGES. Grossly, the tumour is generally large, 10-15 cm in diameter, round to oval, bosselated, and less fully encapsulated than a fibro- adenoma. The cut surface is grey-white with cystic cavities, areas of haemorrhages, necrosis and degene- rative changes. Histologically, the phyllodes tumour is composed of an extremely hypercellular stroma, accompanied by proliferation of benign ductal structures. Thus, phyllodes tumour resembles fibroadenoma except for enhanced stromal cellularity. The histologic criteria ‘used to distinguish benign, borderline and malignant, categories of phyllodes tumour are as under: frequency of mitoses; © cellular atypia; @ cellularity; and ® infiltrative margins. About 20% of phyllodes tumours are histologically malignant and less than half of them may metastasi INTRADUCTAL PAPILLOMA Intraductal papilloma is a benign papillary tumour occurring most commonly in a lactiferous duct or Gharten 23: Tae Breast Wed lactiferous sinus near the nipple. Clinically, it produces serous or serosanguineous nipple discharge. It is most common in 3rd and 4th decades of life. PATHOLOGIC CHANGES. Grossly, intraductal papilloma is usually solitary, small, less than 1 cm in diameter, commonly located in the major mammary ducts close to the nipple. Less commonly, there are multiple papillomatosis which are more frequently related to a papillary carcinoma. Histologically, an intraductal papilloma is charac- terised by multiple papillae having well-developed fibrovascular stalks attached to the ductal wall and covered by benign cuboidal epithelial cells supported by myoepithelial cells. An intraductal papillary carcinoma is distinguished from intraductal papil- Joma in having severe cytologic atypia, pleomor- phism, absence of myoepithelial cells, multilayering and presence of mitotic figures. CARCINOMA OFTHE BREAST Cancer of the breast is among the commonest of human cancers throughout the world. Its incidence and morta- lity are particularly high in developed countries. In the United States, carcinoma of the breast constitutes about 25% of all cancers in females and causes approximately 20% of cancer deaths among females. Cancer of the male breast, on the other hand, is quite rare and comprises 0.2% of malignant tumours (ratio between male-female breast cancer is 1:100). The incidence of breast cancer is highest in the perimenopausal age group and is uncommon before the age of 25 years. Clinically, the breast cancer usually presents as a solitary, painless, palpable lump which is detected quite often by self-examination. Higher the age, more are the chances of breast Jump turning out to be malignant. Thus, all breast lumps, irrespective of the age of the patient must be removed surgically: Currently, emphasis is on early diagnosis by mammography, xero-radio- graphy and thermography. Techniques like fine needle aspiration cytology (FNAC), stereotactic biopsy and frozen section are immensely valuable to the surgeon for immediate pathological diagnosis. Etiology Though extensive clinical and experimental research as well as epidemiologic studies have been carried out in the field of breast cancer, its exact etiology remains elusive. However, based on current status of our knowledge, the following risk factors are considered significant in its etiology:[Lil Sescanc Prmnorcav 1. Geography. The incidence of breast cancer is about six times higher in developed countries than the develo- ping countries, with the notable exception of Japan. ‘These geographic differences are considered to be rela- ted to consumption of large amount of animal fats and high calorie diet by Western populations than the Asians (including Japanese) and Africans. 2. Genetic factors. Recently, much work has been done on the influence of family history and inherited muta- tions in breast cancer: i) Family history: First-degree relatives (mother, sister, daughter) of women. with breast cancer have 2 to 6-fold higher risk of development of breast cancer. The risk is proportionate to a few factors: &_ number of blood relatives with breast cancer; a younger age at the time of development of breast cancer; ® bilateral cancers; and high risk cancer families having breast and ovarian carcinomas. ii) Genetic mutations: About 10% breast cancers have been found to have inherited mutations. These mutations include the following, most important of which is breast cancer (BRCA) susceptibility gene in inherited breast cancer: m BRCA 1 gene located on chromosome 17, a DNA repair gene, is implicated in both breast and ovarian cancer in inherited cases. BRCA1 deletion is seen in about two-third of women with inherited breast cancer having family history but BRCA1 mutation is uncommon in sporadic cases. Men who have mutated BRCAI have increased risk of developing prostate cancer but not of male breast. 1m BRCA 2 gene located on chromosome 13, another DNA repair gene, in its mutated form, has a similarly higher incidence of inherited cancer of the breast (one- third cases) and ovary in females, and prostate in men. In both BRCAI and BRCA2, both copies of the genes (homozygous state) must be inactivated for development of breast cancer. 1 Mulation in TP53 tumour suppressor gene on chromo- some 17 as an acquired defect accounts for 40% cases of sporadic breast cancer in women but rarely in women with family history of breast cancer. TP53 mutation is also seen in Li-Fraumeni syndrome having multiple cancers including breast cancer in young women; others are tumours of the brain, sarcomas, and adrenal cortical tumours. Other mutations seen less commonly in breast cancer include ataxia telangiectasia gene, PTEN (phosphate and tensin) tumour suppressor gene. 3. Oestrogen excess. There is sufficient evidence to suggest that excess endogenous oestrogen or exoge- nously administered oestrogen for prolonged duration is an important factor in the development of breast cancer. Evidences in support of increased risk with oestrogen excess are as follows: i) Women with prolonged reproductive life, with menarche setting in at an early age and menopause relatively late have greater risk. ii) Higher risk in unmarried and nulliparous women than in married and multiparous women. iii) Women with first childbirth at a late age (over 30 years) are at greater risk. iv) Lactation is said to reduce the risk of breast cancer v) Bilateral oophorectomy reduces the risk of develop ment of breast cancer. vi) Functioning ovarian tumours (e.g. granulosa cell tumour) which elaborate oestrogen are associated wil increased incidence of breast cancer. vii) Oestrogen replacement therapy administered postmenopauisal women may result in increased risk’ breast cancer. vili) However, there is no definite increased risk wi balanced oestrogen-progesterone preparations used i oral contraceptives ix) Men who have been treated with oestrogen for tatic cancer have increased risk of developing cancer the male breast Normal breast epithelium possesses oestrogen progesterone receptors. The breast cancer cells many growth factors which are oestrogen-dependi In this way, the interplay of high circulating levels: oestrogen, oestrogen receptors and growth factors bri about progression of breast cancer. 4. Environmental and dietary factors. Among, environmental influences associated with increased ris of breast cancer are consumption of large amounts, animal fats, high calorie foods, cigarette smoking alcohol. The identification of a transmissible retrovi mouse mammary tumour virus (MMTV), also Bittner milk factor transmitted from the infected mot mice to the breast-fed daughter-mice prompted chers to look for similar agent in human breast (Chapter 8). Though no such agent has yet been id fied, there are reports of presence of reverse transcri in breast cancer cells. 5, Fibrocystic change. Fibrocystic change, parti when associated with atypical epithelial hyperp! has about 5-fold higher risk of developing breast subsequently.ter Left breast cancer more common Bilateral tumours 4% Gi TE Anatomic considerations in breast cancer General Features and Classification Cancer of the breast occurs more often in left breast than the right and is bilateral in about 4% cases. Anato- mically, upper outer quadrant is the site of tumour in half the breast cancers; followed in frequency by central portion, and equally in the remaining both lower and the upper inner quadrant as shown in Fig. 23.4. Carcinoma of the breast arises from the ductal epithelium in 90% cases while the remaining 10% origi- nate from the lobular epithelium. For variable period of time, the tumour cells remain confined within the ducts or lobules (non-invasive carcinoma) before they invade the breast stroma (invasive carcinoma). While there are only 2 types of non-invasive carcinoma—intra- ductal carcinoma and lobular carcinoma in situ, there is fa great variety of histological patterns of invasive carcinoma breast which have clinical correlations and prognostic implications. Table 23.1 presents different types of carcinoma of the breast as proposed in the WHO diassification with some modifications. The impor- tant morphological types are described below. A. NON-INVASIVE (IN SITU) CARCINOMA In general, non-invasive or int situ carcinoma is charac- terised histologically by presence of tumour cells within the ducts or lobules without evidence of invasion. Two types of carcinoma int situ are recognised: intraductal carcinoma and lobular carcinoma in situ. 1. Intraductal Carcinoma Carcinoma in sifu confined within the larger mammary ducts is called intraductal carcinoma. The tumour initially begins with atypical hyperplasia of ductal (Charren 23: The Breasr Bayd ‘A. NON-INVASIVE (IN SITU) CARCINOMA. 1. Intraductal carcinoma 2. Lobular carcinoma in sitw B. INVASIVE CARCINOMA 1. Infiltrating (invasive) duct carcinoma-NOS (not otherwise specified) Infiltrating (invasive) lobular carcinoma Medullary carcinoma Colloid (mucinous) carcinoma Papillary carcinoma Tubular carcinoma Adenoid cystic (invasive cribriform) carcinoma Secretory (juvenile) carcinoma 9, Inflammatory carcinoma 10, Carcinoma with metaplasia C. PAGET'S DISEASE OF THE NIPPLE epithelium followed by filling of the duct with tumour cells. Clinically, it produces a palpable mass in 30-75% of cases and presence of nipple discharge in about 30% patients. Approximately a quarter of patients of intra- ductal carcinoma treated with excisional biopsy alone develop ipsilateral invasive carcinoma during a follow- up period of 10 years while the chance of a contralateral breast cancer developing in patients with intraductal carcinoma is far less than that associated with in situ lobular carcinoma. PATHOLOGIC CHANGES. Grossly, the tumour may vary fom a small poorly-defined focus to 3-5 cm diameter mass. On cut section, the involved area shows cystically dilated ducts containing cheesy necrotic material (comedo pattern), or the intraductal tumour may be polypoid and friable resembling intraductal papilloma (papillary pattern). Histologically, the proliferating tumour cells within the ductal lumina may have 4 types of patterns in different combinations: solid, comedo, papillary and cribriform (Fig. 23.5,A): i) Solid pattern is characterised by filling and plugging of the ductal lumina with tumour cells. ii) Comedo pattern is centrally placed necrotic debris surrounded by neoplastic cells in the duct. Papillary pattern has formation of intraductal papillary projections of tumour cells which lack a fibrovascular stalk so as to distinguish it from intra- ductal papilloma. iv) Cribriform pattern is recognised by neat punched out fenestrations in the intraductal tumour,TEE] Systemic Pariovocy Papillary Non-invasive (in situ) carcinoma of breast. 2, Lobular Carcinoma in Situ Lobular carcinoma in situ is not a palpable or grossly visible tumour. Patients of in situ lobular carcinoma treated with excisional biopsy alone develop invasive cancer of the ipsilateral breast in about 25% cases in 10 years as in intraductal carcinoma but, in addition, have a much higher incidence of developing a contralateral breast cancer (30%) PATHOLOGIC CHANGES. Grossly, no visible tumour is identified. Histologically, in situ lobular carcinoma is charac- terised by filling up of terminal ducts and ductules or acini by rather uniform cells which are loosely cohesive and have small, rounded nuclei with indistinct cytoplasmic margins (Fig. 23.5,B). B, INVASIVE CARCINOMA The invasive breast cancer has various morphologic types which have clinical and prognostic correlates. In general, 90% of breast cancers are of larger ductal origin, while the remaining 10% arise from lobular epithelium. 4. Infiltrating (Invasive) Duct Carcinoma-NOS Infiltrating duct carcinoma-NOS (not otherwise specified) is the classic breast cancer and is the most common histologic pattern accounting for 70% cases of breast cancer. In fact, this is the pattern of cancer for which the terms ‘cancer’ and ‘carcinoma’ were first coined by Hippocrates. Clinically, majority of infiltrating duct carcinomas have a hard consistency due to dense colla- genous stroma (scirrhous carcinoma). They are found mote frequently in the left breast, often in the upper outer quadrant (Fig. 23.4). Retraction of the nipple and attachment of the tumour to underlying chest wall may be present. eibritorm Uniform cells PATHOLOGIC CHANGES. Grossly, the tumour is irregular, 1-5 em in diameter, hard cartilage-like mass that cuts with a grating sound. The sectioned surface of the tumour is grey-white to yellowish with chalky streaks and often exiends irregularly into the surroun- ding fat (Fig. 23.6,A). Histologically, as the name NOS suggests, the tumour is different from other special types in lacking a regular and uniform pattern throughout the lesion. A variety of histologic features commonly present are as under ( 23.6,B) (COLOUR PLATE XXXI: CL 124); i) Anaplastic tumour cells forming solid nests, cords, poorly-formed glandular structures and some intraductal foci. ii) Infiltration by these patterns of tumour cells into diffuse fibrous stroma and fat. iii) Invasion into perivascular and perineural spaces as well as lymphatic and vascular invasion. i 2. Infiltrating (Invasive) Lobular Carcinoma Invasive lobular carcinoma comprises about 5% of breast cancers. This peculiar morphologic form dif from other invasive cancers in being mote frequent bilateral; and within the same breast, it may ha\ multicentric origin. PATHOLOGIC CHANGES. Grossly, the appears varies from a well-defined scirrhous mass to a poor! defined area of induration that may remaii undetected by inspection as well as palpation. Histologically, there are 2 distinct features (Fig. 23. i) Pattern—A characteristic single file (Indian linear arrangement of stromal infiltration by tumour cells with very little tendency to g formation is seen. Infiltrating cells may be arranj concentrically around ducts in a target-like pat ii) Tumour cytology—Individual tumour « resemble cells of in sifu lobular carcinoma. TheyCharter 23: Tae Breast We) Diftusely infitrating tumour Infitrating duct carcinoma-NOS. ‘Stromal invasion Intraductal anaplastic cells A, Sectioned surface of breast showing gross appearance of the tumour. B, Microscopic features include formation of solid nests, cords, land-like structures and intraductal growth pattern of anaplastic tumour cells. There is infiltration of densely-collagenised stroma by these cells in a haphazard way. round and regular with very little pleomorphism and infrequent mitoses. Some tumours may show signet- ring cells distended with cytoplasmic mucin. 3. Medullary Carcinoma Medullary carcinoma is a variant of ductal carcinoma and comprises about 1% of all breast cancers. The tumour has a significantly better prognosis than the usual infiltrating duct carcinoma, probably due to good host immune response in the form of lymphoid infiltrate in the tumour stroma. PATHOLOGIC CHANGES. Grossly, the tumour is characterised by a large, well-circumscribed, rounded mass that is typically soft and fleshy or brain-like and hence the alternative name of ‘encephaloid ‘carcinoma’. Cut section shows areas of haemorrhages and necrosis. Histologically, medullary carcinoma is characterised by 2 distinct features: i) Tumour cells—Sheets of large, pleomorphic tumour cells with abundant cytoplasm, large vesicular nuclei and many bizarre and atypical itoses are diffusely spread in the scanty stroma. Stroma—The loose connective tissue stroma is scanty and usually has a prominent lymphoid infiltrate. 4. Colloid (Mucinous) Carcinoma This is an uncommon pattern of breast cancer occurring more frequently in older women and is slow-growing, Colloid carcinoma has better prognosis than the usual infiltrating duct carcinoma. PATHOLOGIC CHANGES. Grossly, the tumour is usually a soft and gelatinous mass with well- demarcated borders. Histologically, colloid carcinoma contains large amount of extracellular epithelial mucin and acini Uniform tumour cells ‘Stromal invasion Indian-file arrangement Invasive lobular carcinoma. Characteristic histologic features are: fone cell wide files of round regular tumour cells (‘indian tile’ arrangement) infitrating the stroma and arranged circumferentially around ducts in a targetike pattern,Systemic PATHOLOGY filled with mucin. Cuboidal to tall columnar tumour cells, some showing mucus vacuolation, are seen floating in large lakes of mucin. 5. Papillary Carcinoma Papillary carcinoma is a rare variety of infiltrating duct carcinoma in which the stromal invasion is in the form of papillary structures. 6. Tubular Carcinoma Tubular carcinoma is another uncommon variant of invasive ductal carcinoma which has more favourable progno Histologically, the tumour is highly well-differen- tiated and has an orderly pattern. The tumour cells are regular and form a single layer in well-defined tubules. The tubules are quite even and distributed in dense fibrous stroma 7. Adenoid Cystic (Invasive Cribriform) Carcinoma ‘Adenoid cystic or invasive cribriform carcinoma is a unique histologic pattern of breast cancer with excellent prognosis, Histologically, there is stromal invasion by islands of cells having characteristic cribriform (fenestrated) appearance. 8. Secretory (Juvenile) Carcinoma This pattern is found more frequently in children and has a better prognosis. The tumour is generally circum- scribed which on histologic examination shows abun- dant intra- and extracellular PAS-positive clear spaces due to secretory activity of tumour cells. 9. Inflammatory Carcinoma Inflammatory carcinoma of the breast is a clinical entity and does not constitute a histological type. The term has been used for breast cancers in which there is red- ness, oedema, tenderness and rapid enlargement. Inflammatory carcinoma is associated with extensive invasion of dermal lymphatics and has a dismal prognosis. 10. Carcinoma with Metaplasia Rarely, invasive ductal carcinomas may have various types of metaplastic alterations such as squamous metaplasia, cartilagenous and osseous metaplasia, or their combinations. Development of squamous cell carcinoma of the breast parenchyma is exceedingly rare and must be separated from lesions of epidermis or nipple region. C. PAGET'S DISEASE OF THE NIPPLE Paget's disease of the nipple is an eczematoid lesion of the nipple, often associated with an invasive or non- invasive ductal carcinoma of the underlying breast. The nipple bears a crusted, scaly and eczematoid lesion with a palpable subareolar mass in about half the cases. Most of the patients with palpable mass are found to have infiltrating duct carcinoma, while those with no palpable breast lump are usually subsequently found to have intraductal carcinoma. Prognosis of patients with ductal carcinoma having Paget's disease is Jess favourable than’ of those who have ductal carcinoma without Paget's disease. The pathogenesis of Paget’s disease of the breast is explained by the following 2 hypotheses: 1, The tumour cells from the underlying ductal carci- noma have migrated up into the lactiferous ducts and invaded the epidermis producing skin lesions. 2. An alternate theory, though less reliable than the former, is that Paget's disease represents a form of carci- noma in situ of the epidermis itself PATHOLOGIC CHANGES. Grossly, the skin of the nipple and areola is crusted, fissured and ulcerated, with oozing of serosanguineous fluid from the erosions. Histologically, the skin lesion is characterised by the presence of Paget's cells singly or in small clusters in. the epidermis. These cells are larger than the epidermal cells, spherical, having hyperchromatic nuclei with cytoplasmic halo that stains positively with mucicarmine. In these respects, Paget's cells are adenocarcinoma-type cells. In addition, the underlying breast contains invasive or non-invasive duct carcinoma which shows no obvious direct, invasion of the skin of nipple. GRADING, STAGING AND PROGNOSIS Histologic grading and clinical staging of breast cai determines the management and clinical course in patients. HISTOLOGIC GRADING. The breast cancers subdivided into various histologic grades dependit upon the following parameters:E 1. Histologic type of tumour. Based on classification described in Table 23.1, breast cancer can be subdivided into 3 histologic grades: i) Non-metastasising—Intraductal and lobular carci: noma in situ ii) Less commonly metastasising—Medullary, colloid, papillary, tubular, adenoid cystic (invasive cribriform), and secretory (juvenile) carcinomas. iii) Commonly metastasising—Infiltrating duct, invasive lobular, and inflammatory carcinomas. 2. Microscopic grade. Widely used system for microscopic grading of breast carcinoma is that of Nottingham modification of the Bloom-Richardson system. It is based on 3 features: i) Tubule formation ii) Nuclear pleomorphism iii) Mitotic count. 3. Tumour size. There is generally an inverse relation- ship between diameter of primary breast cancer at the time of mastectomy and long-term survival. 4. Axillary lymph node metastasis. Survival rate is based on the number and level of lymph nodes involved bby metastasis. More the number of regional lymph nodes involved, worse is the survival rate. Involvement of the lymph nodes from proximal to distal axilla (i.e. level I— superficial axilla, to level I1l—deep axilla) is directly correlated with the survival rate. In this regards, identification and dissection of sentinel lymph node followed by histopathologic examination has attained immense prognostic value (Sentinel lymph node is the first node in the vicinity to receive drainage from primary cancer ic. it stands ‘sentinel’ over the tumour) 5. Oestrogen and progesterone receptors. Oestrogen is known to promote the breast cancer. Presence or absence of oestrogen receptors on the tumour cells can help in predicting the response of breast cancer to endocrine therapy. Accordingly, patients with high levels of oestrogen receptors on breast tumour cells have a better prognosis. A recurrent tumour that is receptor- positive is more likely to respond to anti-oestrogen therapy than one that is receptor-negative. 6. DNA content. Tumour cell subpopulations with aneuploid DNA content as evaluated by flow cytometry have a worse prognosis than purely diploid tumours. CLINICAL STAGING. The American Joint Committee (AJC) on cancer staging has modified the TNM (primary Tumour, Nodal, and distant Metastasis) staging proposed by UICC (Union International for Control of Cancer), (Table 23.2). Spread of breast cancer to axillary lymph nodes occurs early. Later, however, distant spread by lympha- Chapter 23; Tae Breast RAND Pere ee ene ed Stage TIS: In situ carcinoma (in stu lobular, intraductal, Paget's disease of the nipple without palpable lump) Stage Tumour 2 em or less in diameter No nodal spread Stage I: Tumour > 2 cm in diameter Regional Iymph nodes involved Stage IA: Tumour > 5 cm in diameter Regional lymph nodes involved on same side Stage IIB: Tumour > 5 em in diameter Supraclavicular and infraclavicular lymph nodes involved Stage IV; Tumour of any size With or without regional spread but with distant metastasis tic route to internal mammary lymphatics, mediastinal lymph nodes, supraclavicular lymph nodes, pleural lymph nodes and pleural lymphatics may occur. Common sites for haematogenous metastatic spread from breast cancer are the lungs, liver, bones, adrenals, brain and ovaries. Breast is one of the most suspect source of inapparent primary carcinoma in women presenting with metastatic carcinoma. PROGNOSTIC FACTORS IN BREAST CANCER. Based on current knowledge gained by breast cancer screening programmes in the West employing mammo- graphy and stereotactic biopsy, various breast cancer risk factors and prognostic factors have been described ‘These prognostic factors are divided into following 3 groups: 1. Potentially pre-malignant lesions. These conditions are as under: i) Atypical ductal hyperplasia is associated with 4-5 times increased risk than women of the same age. Such lesions are commonest in the age group of 45-55 years. ii) Clinging carcinoma is a related lesion in the duct but different from carcinoma in situ and has lower risk of progression to invasive cancer than jn situ carcinoma. iii) Fibroadenoma is a long-term risk factor (after over 20 years) for invasive breast cancer, the risk being about twice compared to controls 2. Breast carcinoma in situ. Following factors act as determinants: i) Ductal carcinoma in situ (comedo and non-comedo subtypes) is diagnosed on the basis of three histologic features—nuclear grade, nuclear morphology and necro- sis, while lobular neoplasia includes full spectrum of changes of lobular carcinoma in situ and atypical lobularFACTOR L Ro a ip itt) i») wutine histopathology criteria: Histologic type Tumour size (v0 dimensions) Histologic (Nottingham) grading (Score range of 3-9; based on degree of tubule formation-1-3 score, regularity of inucle-1-3 score, and mitoses-1-3 score) Axillary nodal status FAVOURABLE PROGNOSIS Medullary ca,, tubular ca., mucinous (colloid) ca; lobular ca. of low grade Nodal metastasis 10-20% in 1. em size tumour; 10 years survival ®% in node negative Low grade (grade 1) tumour = score 35, ‘moderate grade (grade 11) tumour = score 6-7 Node negative: recurrence rate after 10 years 10-30%; Number of nodes: less than 4; sentinel node negative Lymphatic and/ or vascular incasion ‘Negative for both: good (both extratumoral) vi) Others: 4) Tumour circumscription Good 1) Inflammatory reaction May have some role «) Stromal elastosis “Absence good 4) Intraductal component Presence good ) Skin involoement Absence good IL. Hormone receptor status: estragen-progesterane receptors (ER-PR) IIL Biological indicators: a o Mitotic index (by Ki67, MIB-1) DNA ploidy analysis (aneuploidy, diploidy) ER-PR positive better response to adjuvant therapy Low mitotic count Not related iii) C-ERBB2 (HER2-NEW) ‘Lack of amplification good iv) Epidermal growth factor receptor Underexpression (EGFR) ») Angiogenesis (VEGF, CD31, CD34, Angiogenic activity low microvessel density counts) vi) Oncogene disregulation 8) BRCAI, BRCA2 BRCA negative ») TP53 ‘TP53 positive respond better to chemotherapy and radiotherapy 0 BCL? BCL2 positive good 4) Cathepsin D Absence indicates good prognosis POOR PROGNOSIS Inflammatory ca, Size larger than 1 cm High grade (grade TI) tumour = score 89 Node positive: recurrence rate after 10 years 70%; number of nodes: more than 4; sentinel node positive Positive for one or both: poor Poor Controversial Presence poor Absence poor Presence poor ER-PR negative poor response to adjuvant therapy High mitotic count Not related Presence of amplification Overexpression High angiogenic activity BRCA positive P53 negative respond spoorly to chemotherapy and radiotherapy BCL2 negative poor Presence renders poor prognosis hyperplasia. Ductal carcinoma int sit is more impor- tant and demands most attention. Comedo type of it situ carcinoma has higher recurrence rate. ii) Breast conservative therapy is used more frequently nowadays in carcinoma jn situ which requires consi- deration of three factors for management: margins, extent of disease, and biological markers. The biological markers such as TP53 and BCL 2 have low positivity in high- grade in situ ductal carcinoma and likelihood of recurrences after conservative surgery. 3. Invasive breast cancer. Prognostic and predictive factors for invasive breast cancer have been extensively studied by univariate analysis (examining single fa separately) as well as by multivariate analysi (comparing the value of various factors included in study). These can be broadly divided into 3 groups: 1, routine histopathology criteria; 2. hormone receptor status; and 3. biological indicators. j ‘A summary combining all these factors is given i Table 23.3.