A 44-year-old woman comes to the office due to a breast mass. Physical examination reveals a hard, fixed mass in the right breast with palpable ipsilateral axillary lymphadenopathy. Mammography demonstrates a spiculated right-sided breast lesion. The patient undergoes mass resection and axillary lymph node dissection. Histopathologic examination shows ductal adenocarcinoma with local spread to the axillary nodes. The ability of the tumor to reach draining lymph nodes is facilitated by which of the following changes at the primary tumor site?

Question

A 44-year-old woman comes to the office due to a breast mass.  Physical examination reveals a hard, fixed mass in the right breast with palpable ipsilateral axillary lymphadenopathy.  Mammography demonstrates a spiculated right-sided breast lesion.  The patient undergoes mass resection and axillary lymph node dissection.  Histopathologic examination shows ductal adenocarcinoma with local spread to the axillary nodes.  The ability of the tumor to reach draining lymph nodes is facilitated by which of the following changes at the primary tumor site?

Quizplus · Accepted Answer

Tumor cells are generally sequestered in the tissue of origin until they develop the following adaptations: Loss of cell-cell adhesion: Normal epithelial cells tightly adhere to each other using cadherin glycoproteins. Tumor cells down-regulate cadherin (eg, E-cadherin), which frees individual cells to leave the site of origin (Choice D). Detachment from the basement membrane: Basal epithelial cells tightly adhere to the basement membrane using integrin receptors, which anchor the basal end of the cytoskeleton to external collagen, laminin, and fibronectin. This attachment helps maintain cellular differentiation and limits excessive cellular growth. Tumor cells loosen their attachment to the basement membrane by reducing the expression of integrin receptors. Unlike normal epithelial cells, tumor cells can usually survive without cell-cell or cell-basement membrane adhesion due to antiapoptotic genetic mutations. Destruction of extracellular matrix: The basement membrane serves as a mechanical barrier that separates tumor cells from blood vessels and lymphatics in the interstitial matrix. In order to penetrate the basement membrane, tumor cells increase production of type IV collagenases such as matrix metalloproteinase (MMP). They also usually limit the release of MMP inhibitors, which further amplifies basement membrane degradation (Choice B). Migration: Tumor cells secrete autocrine motility factors and express receptors for stromal chemotactic factors. They also frequently increase the expression of non-integrin laminin receptors at their leading end, which promotes propulsion through the extracellular matrix (Choice A). Dissemination: Tumor cells penetrate blood and lymph vessels using MMPs/proteases and enter the vessel lumen. Because individual cancer cells are highly susceptible to destruction by shearing forces and the adaptive/innate immune response, they typically aggregate in clumps or attach to platelets and form emboli. They also express factors that allow them to localize to specific sites; CD44, a localization receptor normally found on T lymphocytes, is frequently expressed on tumor cells that disseminate to lymph nodes. Educational objective: Malignant cells undergo several changes to metastasize from the site of origin. They detach from other cells by down-regulating cadherins and detach from the basement membrane by down-regulating integrins. They secrete collagenases to create a path through the extracellular matrix and then enter the bloodstream and/or lymphatic system to disseminate.

A 44-Year-Old Woman Comes to the Office Due to a Breast