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Breast Cancer

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Pathophysiology

Summary

Breast cancer is the predominant cancer in women and a leading cause of cancer-related mortality. Breast cancer is complex interplay of genetic and environmental elements, making early detection and tailored management imperative.

Genetic risk factors such as family history, mutations in BRCA1 & BRCA2, and Li-Fraumeni syndrome are paramount. BRCA1 & BRCA2 are autosomal dominant tumor suppressor genes that follow the ’two-hit' hypothesis. Li-Fraumeni syndrome, also autosomal dominant, arises from mutations in the p53 tumor suppressor gene and predisposes to a broader spectrum of malignancies, including those of the breast, bone, brain, and adrenal glands.

Environmental risk factors include postmenopausal estrogen exposure, obesity, early menarche, and late menopause. Obesity exacerbates risk through aromatase activity in adipocytes, converting androstenedione to estrone and resulting in elevated estrogen levels. Extended exposure to endogenous estrogen, influenced by early menarche, late menopause, nulliparity, and advanced maternal age at first pregnancy, further contribute to cancer risk. Notably, breastfeeding offers a protective effect against the disease.

Molecularly, the expression of progesterone receptors (PR), HER2/NEU proto-oncogene, and estrogen receptors (ER) can be amplified in breast cancers. ‘Triple negative’ breast cancer lacks overexpression of PR, ER, & HER2/NEU, and typically has a poorer prognosis.

Precursor lesions, specifically ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), precede invasive carcinomas. DCIS originates in terminal ducts and fills the lumen without breaching the basement membrane. It is often detectable on mammography due to microcalcifications and a tendency for central necrosis. LCIS also arises from terminal ducts, but migrate to fill lobular spaces. LCIS shows no mammographic evidence of mass or calcifications. On histology, it features round nuclei clustering within the lobules. Surgical intervention remains the cornerstone for managing both DCIS and LCIS.

Invasive ductal carcinoma is the most common type of breast cancer, and is typified by malignant cells breaching the ductal basement membrane. It often presents as a fixed, painless mass with irregular contours, primarily in the upper outer breast quadrant. Signs like skin dimpling or nipple inversion may also be noted, which are caused by tumor-induced fibrosis and shortening of Cooper's ligaments. On mammography, a spiculated ‘spiky’ mass accompanied by clustered microcalcifications is typical. Histologically, the cancer shows nests of irregular, dark purple cells encased in a dense fibrous stroma, indicative of a desmoplastic reaction.

Invasive lobular carcinoma is second in incidence, and manifests as a palpable masses and mammographic densities. It tends to be bilateral and multifocal. Histologically, the tumor cells align in an orderly row.

Inflammatory breast cancer is a rare and highly aggressive form, and presents with ‘peau d’orange,' erythematous, thickened, and dimpled appearance. This is due to dermal lymphatic invasion by poorly differentiated tumor cells, leading to rapid lymphatic spread and early metastasis.

Other specialized forms include medullary carcinoma, defined by its poorly differentiated cells and lymphocytic infiltration; mucinous carcinoma, recognized by its gelatinous mass composed of tumor cells in mucinous pools; and tubular carcinoma, distinguished by well-formed tubules on histology and a favorable prognosis.

Paget disease of the breast is a rare disorder that causes eczema-like changes to the nipple and areola, and occurs when malignant cells migrate through the lactiferous ducts and into the epidermis of the nipple, overlying a breast carcinoma. On histology, malignant Paget cells—large adenocarcinoma cells with clear cytoplasm and dark nuclei—infiltrate the nipple's epidermis. A similar condition, extramammary Paget disease, can manifest in the genital area but is not typically associated with underlying malignancy.

For tumors overexpressing estrogen receptors, selective estrogen receptor modulators (SERMs) like tamoxifen or raloxifene are therapeutic options. Also noteworthy is male breast cancer, which frequently occurs in men harboring BRCA2 mutations and may also be estrogen receptor-positive.

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FAQs

What is the role of BRCA1 and BRCA2 mutations in breast cancer?

BRCA1 and BRCA2 are autosomal dominant tumor suppressor genes that play a critical role in the risk of developing breast cancer. Mutations in these genes significantly elevate the likelihood of breast cancer occurrence. These mutations follow the "2-hit" hypothesis, meaning that individuals inherit one mutated BRCA allele and are at risk of developing breast cancer if the second allele undergoes a random somatic mutation during their lifetime. Because these mutations are autosomal dominant, having even one mutated allele significantly increases the risk of breast cancer.

What are some known risk factors for breast cancer?

Several risk factors contribute to the likelihood of developing breast cancer. Genetic factors include a family history of the disease, mutations in the BRCA1 and BRCA2 genes, and Li-Fraumeni syndrome. Non-genetic factors include exposure to exogenous estrogen after menopause, obesity, early menarche, late menopause, nulliparity, and older age at first pregnancy. Obesity is also a common risk factor, as the aromatase enzyme in adipocytes convert androstenedione to estrone, which can lead to excessive estrogen.

What is Li-Fraumeni syndrome and how does it relate to breast cancer?

Li-Fraumeni syndrome is an autosomal dominant genetic disorder caused by a mutation in the p53 tumor suppressor gene, which functions as a checkpoint in the cell cycle. This syndrome significantly increases the risk of developing various types of tumors, including those in the bone, brain, and adrenal glands, in addition to breast cancer. Because p53 plays a crucial role in preventing cancerous growth, mutations in this gene can lead to uncontrolled cell proliferation, elevating the risk of breast cancer among other malignancies.

How are selective estrogen receptor modulators (SERMs) used in the treatment of breast cancer?

Selective estrogen receptor modulators (SERMs) like Tamoxifen and Raloxifene are used to treat breast cancers that overexpress estrogen receptors. SERMs bind to these receptors and act as antagonists in breast tissue, inhibiting the cancer-promoting effects of estrogen. These medications offer targeted therapy for certain types of breast cancer, making them a valuable component of treatment plans.

What are the characteristics of inflammatory breast cancer?

Inflammatory breast cancer is a rare but aggressive form of breast cancer that presents with ‘peau d’orange,' an erythematous, thickened, and dimpled appearance of the overlying skin due to lymphedema and inflammation. On histology, this type of cancer displays dermal lymphatic invasion by poorly differentiated tumor cells. It tends to metastasize early, primarily due to its early invasion of the lymphatic system, making timely diagnosis and treatment crucial.