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Breast cancer
Pathology

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	Breast Cancer
	- Introduction - Causes - Clinical Picture - Screening - Diagnosis - Pathology - Staging - Treatment

Doubling time

Doubling times for primary breast cancer ranged from 44 to more than 1,800 days, with a mean of 212 days. Metastatic lesions may have a slightly faster average rate of growth than primary tumors.

Classification

The World Health Organization classification of breast tumors organizes both benign and malignant lesions by histologic pattern. Epithelial tumors comprise the largest group, including intraductal papilloma, adenomas, intraductal and lobular carcinoma in situ, invasive (ductal and lobular) carcinoma, and Paget disease of the nipple. Invasive ductal carcinoma is by far the most common type.

The relative frequency of malignant breast cancers are:

• Ductal carcinoma:78%

• Lobular carcinoma: 9%
  Alveolar & mixed types are bilateral. Solid & signet ring have worse prognosis than IDC with high tendency to metastasize.

• Comedocarcinoma: 5%

• Medullary: 4%.

• Inflammatory: worst prognosis

• Paget's: unilateral eczema of the nipple.

• Other

The pathological classification of breast cancer is based on on the anatomic or structural units
present in the female breast. These units consist of large, medium, and small ducts from which a variety of tumor types arise.

1. Large ducts

Noninvasive cancer

Tumors arising from duct epithelium may be found only within the lumen of the ducts of origin;
that is, the carcinomas are intraductal and do not penetrate the basement membrane or invade surrounding stroma. Most frequently, such tumors arise from large ducts and may present as several types.

Ductal carcinoma in situ (DCIS)

The noninvasive variety of ductal carcinoma, referred to as intraductal carcinoma or ductal
carcinoma in situ (DCIS), is a proliferation of a subgroup of epithelial cells confined to the mammary ducts without light microscopic evidence of invasion through the basement membrane into the stroma.

DCIS, like invasive ductal carcinoma, occurs more frequently in women, although it accounts for approximately 5% of all male breast cancers. The average age at diagnosis of DCIS is 54-56 years, which is approximately a decade later than the age at presentation for LCIS.

The clinical signs of DCIS include a mass, breast pain, or bloody nipple discharge. On mammography, the disease most often appears as microcalcifications.

The risk of developing an invasive carcinoma following a biopsy-proven diagnosis of DCIS is between 25% and 50%. Virtually all invasive cancers that follow DCIS are ductal and ipsilateral and generally present in the same quadrant within 10 years of the diagnosis of DCIS. DCIS is less likely than LCIS to be bilateral and has approximately a 30% incidence of multicentricity. DCIS is considered a more ominous lesion than LCIS and appears to be a more direct precursor of invasive cancer.

A variety of histologic patterns of DCIS have been recognized. The most frequently encountered are:

• Comedo

• Cribriform

• Solid

• Papillary

• Micropapillary

The different histologic patterns have been associated with differences in biologic behavior. Some researchers have divided DCIS into two subgroups: comedo and noncomedo types. As compared with the noncomedo subtypes, the comedo variant has a higher proliferative rate, overexpression of HER-2/neu, and a higher incidence of local recurrence and microinvasion.The role of assays for estrogen and progesterone receptors (ER and PR) in DCIS has not been established.

Comedocarcinoma: is characterized by ducts that are dilated and filled with carcinoma cells. These are necrotic and can be expressed as semisolid necrotic plugs. Such cancers are not usually regarded as a separate cell type but rather represent a descriptive variant of intraductal carcinoma. Patients whose DCIS exhibits comedo features have been shown to have increased rates of local recurrence and may progress more rapidly to invasive breast cancer compared to other types.

Papillary carcinoma: If they grow into the ducts with a papillary configuration, they are recognized as papillary carcinomas. Such lesions are rare, accounting for about 1% of breast cancers. Histologically, pleomorphic duct epithelial cells with disturbed polarity can be demonstrated, as can their “heaping up” into papillae. Difficulty may be encountered in differentiating a papillary carcinoma from a benign atypical papilloma.

Papillary carcinomas rarely invade the surrounding stroma. A survival rate approaching
100% may be anticipated upon complete excision of such tumors. When these tumors do invade surrounding tissue, they grow rather slowly and attain considerable bulk. Skin and fascial attachments are unusual, and axillary node involvement is a late feature. Clinically, noninvasive tumors are found to be movable, circumscribed lesions that have a soft consistency not unlike that of fibroadenomas.

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Invasive cancer

1. IDC NOS

Infiltrating duct carcinomas in which no special type of histologic structure is recognized are designated “not otherwise specified” (NOS) and are the most common duct tumors, accounting for almost 80% of breast cancers. They are characterized clinically by their stony hardness to palpation. When they are transected, a gritty resistance is encountered, and the tumor retracts below the cut surface. Yellowish, chalky streaks that represent necrotic foci are observed. Histologically, varying degrees of fibrotic response are present. As a rule, they do not become large. They frequently metastasize to axillary lymph nodes, and their prognosis is the poorest of the various tumor types. More than half (52.6%) of breast cancers are pure infiltrating duct lesions (NOS).

Special types of IDC

Medullary carcinoma

Medullary carcinoma, composing 5 to 7% of all mammary carcinomas, often attains large dimensions. This tumor is formed by cells of relatively high nuclear grade, and usually exhibits
an extensive infiltration of the tumor by small lymphocytes. Medullary carcinomas have a relatively well-circumscribed border, sometimes described as a “pushing” border, in contrast to
the NOS tumors in which small nests of cells tend to infiltrate the adjacent stroma more extensively. A study of medullary cancer using 336 typical and 273 atypical medullary breast
cancers from 6,404 patients enrolled in various Stage I and Stage II National Surgical Adjuvant Breast Project (NSABP) trials indicated that the survival of patients with typical medullary cancers was better than that for patients with NOS invasive ductal carcinomas. Survival was comparable for those with atypical medullary and NOS types.

Tubular carcinoma

Tubular carcinoma is an invasive carcinoma in which tubule formation is highly prominent. This tumor has a low nuclear grade with some cell polarity. Its prognosis is favorable, and, when combined with small size, it is a highly curable tumor.

Mucinous carcinoma

Mucinous or colloid carcinoma, which composes about 3% of all mammary carcinomas, is characterized on microscopy by its nests and strands of epithelial cells floating in a mucinous matrix. It usually grows slowly and can reach bulky proportions. When the tumor is predominantly mucinous, the prognosis tends to be good. Two entities represent special manifestations of mammary carcinoma.

Papillary carcinoma: See above.

2. Small ducts

Noninvasive cancer

Lobular carcinoma in situ

With the increased use of mammography, a much higher proportion of noninvasive cancers is being detected. Lobular CIS consists of a neoplastic proliferation of cells in the terminal breast ducts and acini. It is characterized by small and round cells of low nuclear grade that fill and expand lobules without penetration of the basement membrane. Though these lesions are low grade, there is a 15-30% risk for development of invasive carcinoma in the same or the opposite breast. This risk is greatest within 10-15 years after the diagnosis is established. Whereas DCIS often accompanies invasive ductal carcinoma, and may well be its usual precursor, LCIS may be followed by invasive ductal or invasive lobular carcinomas in either breast. LCIS thus is more a systemic marker than a local precursor. Recent investigations suggest that LCIS is heterogeneous, and there is biologic variability. Therefore, there may be certain subtypes of LCIS that are more likely to progress to invasion.

There is no mass lesion or mammographic abnormality associated with this disease. The pathologist is the only physician who makes this diagnosis. LCIS is found in 0.5-3.8% of otherwise benign breast biopsies. The true incidence of lobular carcinomas is uncertain. It has been emphasized that noninvasive mammary carcinomas make up almost 5% of all neoplastic lesions of the female breast and that LCIS accounts for about 50% of these, or 2.5 to 2.8% of all tumors. The incidence of LCIS has doubled over the past 25 years and is now 2.8 per 100,000 women. In the past, the peak incidence of LCIS was in women in their 40s. Over the past 3 decades, the peak incidence has increased to the 50s. The incidence of LCIS decreases in women who are in their 60s-80s. This may be related to the use of hormone replacement therapy (HRT).

Pathology: Most commonly in both breasts in multifocal and multicentric. If LCIS is found in a breast, >50% will have residual LCIS in the ipsilateral breast and >1/3 will have LCIS in the contralateral breast. Classically, involved acini are filled and distended by a uniform population of cells. At least half of the acini are involved within the lobular unit (this distinguishes it from atypical lobular hyperplasia in which fewer than half of the acini are expanded or distorted by a uniform population of lobular cells.

Lobular carcinoma

Lobular carcinoma arises from the small end ducts of the breast.

Invasive lobular carcinoma is similar to LCIS but the lesion extends beyond the boundary of the lobule or terminal duct from which it arises. Often the small cells interdigitate between collagen bundles in a single line, so-called “Indian file.” At other times, lobular carcinoma may be nearly indistinguishable from the conventional infiltrating duct carcinoma. The increase in invasive lobular carcinoma peaks in women in their 70s. It is associated with both synchronous and metachronous contralateral primary tumors in 30% of the cases.

Inflammatory breast cancer

Inflammatory breast cancer, or “dermal lymphatic carcinomatosis”, is an uncommon form of rapidly advancing breast cancer that usually accounts for approximately 1% to 3% of all breast cancer diagnoses. Inflammatory breast cancer causes the breast to appear swollen and inflamed. This appearance is often caused when cancer cells block the lymphatic vessels in the skin of the breast, preventing the normal flow of lymph fluid and leading to reddened, swollen and infect-looking breast skin—hence the designation "inflammatory" breast cancer. It can easily be confused with mastitis an infection of the breast ducts. To increase the confusion with infection, resulting in treatment with antibiotics, and sometimes, but not always, the antiobiotic treatment changes the appearance of clinical symptoms.  The reason for an apparent response to antibiotics when IBC is present is not known, and may delay the diagnosis of IBC.

With inflammatory breast cancer, the breast skin has a thick, pitted appearance that is classically described as peau d’orange (resembling an orange peel). Sometimes the skin develops ridges and small bumps that resemble hives. These features may be present at the time of primary diagnosis or as part of the clinical picture of recurrent breast cancer.

Biopsies of the erythematous areas and adjacent normal-appearing skin reveal poorly differentiated cancer cells filling and obstructing the subdermal lymphatics. Inflammatory cells are rarely present. Patients typically have signs of advanced cancer, including palpable axillary nodes, supraclavicular nodes, and/or distant metastases.

Paget's disease of the nipple

This disease presents as a persistent dermatitis of the nipple. Clinically, the patient presents with a relatively long history of eczematoid changes in the nipple, with itching, burning, oozing, and/or bleeding which is often unresponsive to topical steroid and antibiotics. The nipple changes are associated with an underlying carcinoma in the breast that can be palpated in about two-thirds of the patients. The alert physician may biopsy the nipple revealing the characteristic changes. Clinically impalpable and radiologically undetectable disease is present in about 40% of the patients. Most commonly, this is an infiltrating ductal carcinoma but occasionally a ductal carcinoma in situ (DCIS) may be present. Overall, this cancer is rare, comprising 1-4% of all patients with breast carcinoma.

Under the microscope, there is a proliferation of malignant epithelial cells scattered throughout the epidermis. The cells have abundant pale staining cytoplasm surrounding a hyperchromatic nucleus with prominent nucleoli.

Other histological types

Several other histologic types of mammary carcinomas have been described but are rarely encountered. Adenocystic carcinoma, carcinosarcomas, pure squamous cell carcinoma, metaplastic carcinomas (carcinoma with osseous or cartilaginous stroma), basal cell carcinomas, and so-called lipid-rich carcinomas have been observed. Because of their rarity, clinical correlates are practically nonexistent.

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