Pathology > Study Images > Gynecologic > Breast > Malignant Neoplasms
Objectives Anat & Hist Hormones Inflammatory Cond. Nonneoplastic Cond. Benign Neoplasms Malignant Neoplasms

VI. Malignant Neoplasms

Objectives:

After completing this section you will know:

  • site and relative distribution of cancer within the breast
  • the epidemiological features and predisposing factors of breast cancer
  • the main groups and subtypes of breast cancer and which is most common
  • clinical and histologic features of the common subtypes
  • prognostic factors in breast cancer and prognosis associated with the common subtypes

Epidemiology

Age: There is a steady increase in the incidence of breast cancer, as women grow older. The age-specific incidence rate is highest in postmenopausal women.

Family history: The relative risk of breast cancer in a woman with breast cancer in first-degree relative (mother, sister, or daughter) ranges from 1.5 to 2.5.

Reproductive factors: The younger a woman’s age at menarche, the higher her risk of breast cancer. For each 2 years delay in onset of menstrual activity, the risk is reduced by about 10%.

The earlier a woman has her first birth, the lower her lifetime risk for breast cancer. This is independent of parity. A woman who has her first birth after 30 years has an increased risk. A nulliparous woman has increased risk.

The later a woman’s age at menopause, the higher her risk of breast cancer. Women who had their menopause after 55 years have 2 times the risk of those who had their menopause before 45 years.

Previous cancer: Women who have had a breast cancer have a 10-fold increased risk of developing a second primary breast cancer.

Atypical hyperplasia: See above.

Geographic factors: Breast cancer is more common in Western industrialized countries than in developing countries.

Classification

Carcinoma of the breast is divided into noninvasive and invasive carcinomas.

  1. Noninvasive carcinoma (Carcinoma in situ)

This is epithelial proliferation that is still confined to the TDLU, has not invaded beyond the basement membrane and is therefore incapable of metastasis. There are two subtypes: 1) Ductal carcinoma in situ (DCIS) or intraductal carcinoma and 2) Lobular carcinoma in situ. The incidence in autopsy studies is about 20%.

Ductal carcinoma in situ (Intraduct carcinoma)

DCIS comprises a heterogeneous group of noninvasive neoplastic proliferation with diverse morphologic appearances and risks of subsequent recurrences and development of subsequent invasive carcinoma. The tumor distends and distorts the ducts in the TDLU so that the terminal ducts enlarge and resemble large ducts. Although the tumor is confined to the TDLU, neoplastic cells can spread throughout a ductal system and produce extensive lesions involving an entire sector of a breast. Involvement of a main lactiferous duct and thence the nipple leads to the development of Paget’s disease of the nipple (see below). DCIS occurs throughout the age range of breast carcinoma with mean age at diagnosis between 50 and 59 years, similar to the mean age of women with invasive ductal carcinoma. Mammography is a very sensitive diagnostic procedure for detecting DCIS, as a substantial proportion is not palpable. Mammographically detected microcalcifications are found in 72 to 98% of DCIS. The tumor is divided into two histologic types: comedo and cribriform/micropapillary carcinoma.

Comedocarcinoma

Comedocarcinoma involving multiple ducts produces a firm mass, which may be well defined, and shows white-to-pale yellow flecks of pasty necrotic debris which extrude from the cut surface on pressure hence the name comedocarcinoma. Calcifications are frequent and produce a characteristic branching pattern on mammography.

Histologically, comedocarcinoma grows in a solid pattern with a central area of necrosis. Large pleomorphic tumor cells with irregular nuclei, commonly with prominent nucleoli characterize the tumor.

The tumor spreads extensively through ducts well beyond the extent of its visible confines. Thus excision margins frequently contain tumor and the technical difficulties of ensuring complete excision frequently demand mastectomy.

Cribriform/Micropapillary carcinoma

These tumors are differentiated by their growth patterns as they form papillary structures and small, regular fenestrations (giving a sieve-like appearance, hence the name cribriform). The tumor cells are smaller and more uniform compared to comedocarcinoma and lack necrosis. However, this variant of DCIS is often admixed with the comedo type.


Cribriform DCIS. Note regular punched out fenestrations and distension of duct, which is filled tumor cells.


Cribriform DCIS (center) surrounded by comedo-type DCIS.


Micropapillary carcinoma.

Clinical behavior

The two types of DCIS differ markedly in their risk of subsequent invasive carcinoma. Comedocarcinoma has essentially a 100% chance of becoming invasive if left untreated. Pure cribriform/micropapillary carries only a 30% chance of invasive carcinoma.

Lobular carcinoma in situ

Lobular carcinoma in situ (LCIS) does not form a palpable mass and cannot be detected clinically, felt at operation or seen grossly on pathological examination. Although LCIS may have microcalcifications, these are infrequent and so mammography has not been useful for detecting it. The tumor presents as a coincidental finding in breast tissue removed for other reasons. The tumor is found in 1 to 6% of breast biopsies and forms 30 to 50% of noninvasive carcinomas found in biopsies. The age distribution does not differ significantly from that for invasive carcinoma ranging from 44 to 54 years. The disease tends to be bilateral and multicentric. In biopsies about 40% of cases are bilateral while in mastectomy cases about 67% are bilateral.

LCIS shows a proliferation of cells that fill and distend the TDLU. The cells are larger than normal ductular cells, loosely cohesive and uniform with regular round to oval nuclei, small nucleoli and moderate pale cytoplasm. They are arranged in an orderly fashion and there are very few or no mitoses.

Clinical behavior

If LCIS is left untreated, about 30% of women develop an invasive cancer within 20 years of diagnosis. The invasive cancer has a 50% chance of occurring in the breast contralateral from the one containing the LCIS. The invasive cancer may be ductal or lobular. LCIS is therefore a marker of increased cancer in both breasts.

NOTE: The use of the term carcinoma for these lesions has excited controversy. Their malignant nature has been questioned. The implication of the term is that the lesions have the capacity to progress and invade. It is now clear that such progression to invasive lesions does not occur clinically in the lifetime of all patients even when not treated. It is likely that foci of these lesions may remain dormant for years or even indefinitely. It is possible that some may regress. There are at the present no methods to accurately predict the likelihood of progression to invasive carcinoma and the quandary of how to treat these lesions largely result from this. However, one thing is certain, that these lesions place a woman at a high risk of developing invasive carcinoma.

  1. Invasive carcinoma

Invasive breast carcinoma is breast tumor that has extended across the basement membrane. This permits access to lymphatics and vessels and the potential distant metastases and thereby a lethal outcome. There are several different types of invasive carcinoma. Invasive breast carcinoma is subdivided into:

  • Invasive ductal carcinoma not otherwise specified (NOS)
  • Invasive lobular carcinoma
  • Medullary carcinoma
  • Colloid or mucinous carcinoma
  • Tubular carcinoma

There are other subtypes, which are very rare and will not be discussed.

Distribution


Breast cancer. Locations and distribution.

Question: Why is the upper outer quadrant the commonest site for breast cancer?

Invasive ductal carcinoma NOS

Invasive ductal carcinoma not otherwise specified is the commonest type of breast cancer, forming up to 80% of these cancers. Most of these tumors excite a pronounced fibroblastic stromal reaction to the invading tumor cells producing a palpable mass with hard consistency (hence scirrhous carcinoma), which is the most common presentation. The tumor shows an infiltrative attachment to the surrounding structures and may cause dimpling of the skin (due to traction on suspensory ligaments) or nipple retraction. Cut surface is gritty and shows irregular margins with stellate infiltration and foci of yellow, chalky streaks.


Invasive ductal carcinoma

Histologically, the tumor cells are larger than normal epithelium, and can assume a variety of patterns such as glandular formation, cords of cells, broad sheets of cells or a mixture of all these, usually within a dense stroma. The tumors range from well differentiated, in which there is glandular formation, to poorly differentiated, containing solid sheets of pleomorphic neoplastic cells (see grading below).


Invasive ductal carcinoma. Low power view showing infiltrative margins.


Invasive ductal carcinoma showing dense fibroblastic stroma.

Invasive lobular carcinoma

Lobular carcinoma is the second most common type of invasive breast cancer forming up to 10% of breast cancers. The tumor may occur alone or in combination with ductal carcinoma. It tends to be bilateral more often than ductal carcinoma and multicentric.

The amount of stromal reaction to the tumor varies from dense desmoplasia to little reaction and therefore the presentation varies from a discrete mass to a subtle, diffuse indurated area.

The cancer cells are small, bland and uniform, about the size of normal ductular epithelial cells. Classically, the cells tend to infiltrate as individual rows (single or Indian file) and may form concentric arrays (targetoid pattern). Occasionally, a solid pattern or cords of cells are produced. In about 10% of cases, tumors have mixed features of invasive ductal and lobular carcinomas.


Invasive lobular carcinoma showing infiltrating single rows of cells (Indian file pattern).


Invasive lobular carcinoma showing solid and single cell patterns. Note targetoid pattern in the center of the lesion.

Medullary carcinoma

This subtype of breast cancer presents as a circumscribed mass. It does not produce any fibroblastic reaction and therefore is soft and fleshy (encephaloid). On section foci of necrosis and hemorrhage are evident.

Microscopically, the tumor is composed of solid sheets of cells forming a syncytium with large pleomorphic nuclei, prominent nucleoli and frequent mitoses. There is scant fibrous stroma. Moderate to large numbers of lymphocytes and plasma cells surround the sheets of tumor cells.

Mucinous or Colloid carcinoma

Mucinous carcinoma tends to occur in older women. It is sharply circumscribed, lacks fibrous stroma, is soft and gelatinous and has a glistening cut surface.

It may be pure in which more than 75% of the tumor is mucinous or mixed in which it is associated with other types of invasive breast carcinoma. The mucinous tumor is composed of small islands, occasionally forming glands, and isolated tumor cells floating in pools of extracellular mucin.

Tubular and Cribriform carcinomas

Tubular carcinoma is composed of small glands or tubules that take variable shapes. The distribution of the glands is haphazard and a single layer of cells lines each gland. Cribriform carcinoma grows as rounded and angular masses of uniform tumor cells embedded in variable amounts of fibrous stroma with sharply outlined, round or oval glandular spaces distributed throughout the tumor aggregates giving a sieve-like growth pattern. Both tumors may be mixed with other types but in their pure form are locally invasive in the breast and only a small proportion (5-10%) metastasize to lymph nodes.

Paget’s disease of the nipple

Paget’s disease of the nipple presents with an eczematous area of the nipple, which may be subtle or form an obviously eroded, weeping lesion. The underlying process is population of the epidermis of the nipple with neoplastic cells, which are identical to a DCIS in the underlying ducts or, less commonly, with an invasive ductal carcinoma deeper within the breast. In advanced lesions, the process may extend to involve the areola and adjacent skin.

The histologic hallmark of Paget’s disease of the nipple is the infiltration of the epidermis by large neoplastic cells with abundant clear or pale cytoplasm and nuclei with prominent nucleoli. The cells usually stain positively for mucin.

Question: In which other part(s) can a similar lesion occur?

The prognosis of Paget’s disease depends on the prognosis of the underlying carcinoma.

Clinical behavior of breast cancers

The prognosis of breast cancer depends on several factors including the histologic type of the tumor, the grade, the size of the tumor, the presence or absence of lymph node metastases, and the presence or absence of hormone receptors.

Histologic type: Infiltrating ductal and lobular carcinomas have the worse prognosis, medullary and mucinous have intermediate and tubular and cribriform have the most favorable prognoses.

Stage: This is a combination of size and lymph node status. Tumor size less than 2 cm is associated with a favorable prognosis. The single most important prognostic indicator is the lymph node status. Negative lymph nodes have the best prognosis. Involvement of 1 to 3 lymph nodes has an intermediate prognosis and 4 or more positive nodes have the worse prognosis.

Grade: This is done by the pathologist. Grading separates tumors into three categories according to the amount of well formed tubules, the degree of nuclear pleomorphism, and the number of mitoses as follows:

Objectives Anat & Hist Hormones Inflammatory Cond. Nonneoplastic Cond. Benign Neoplasms Malignant Neoplasms