Intratumoral Microvascular Density

Intratumoral microvessel density (MVD) has been extensively studied in a variety of solid tumors and has been reported as a powerful independent prognostic factor in many tumor types (29). Several clinical reports have suggested a strong correlation between intratumoral MVD and the development of metastases, primary tumor growth, and the expression of certain angiogenic peptides (30). A variety of methods for assessing MVD have been reported (31), but the most commonly used is that proposed by Weidner et al. (32). Analysis of sections from paraffin blocks containing invasive tumor specimens are stained with hematoxylin and eosin. The sections are then stained with endothelial-cell-specific antibodies, such as anti-FVIII-Rag, anti-CD31, and anti-CD34. (The optimal endothelial cell antibody stain is also a subject of debate, since the sensitivity and specificity of individual antibodies is variable, as is their ability to stain intratumoral lymphatics [31].) Vascular "hot spots" are identified by scanning the section under low-power magnification (x 10-100). The rationale for identifying vascular hot spots is based on the notion that these areas of the tumor probably represent the location where angiogenic clones of tumor cells reside, and are most likely to enter the circulation and metastasize to distant sites. Once hot spots are identified, the magnification is increased to x200-400, corresponding to a field size of approx 0.74 mm2. Any highlighted endothelial cell or cluster of cells is counted as a distinct microvessel.

The relationship between intratumoral MVD and prognosis has been reported for several different tumor types, but the greatest number of reports have been in primary operable breast cancer. Gasparini (33) recently reviewed breast cancer reports accounting for 3200 cases of breast cancer. A statistically significant relationship between intratumoral MVD and relapse-free survival (RFS) and overall survival (OS) was seen in 69 and 80% of reports, respectively. Other ways of assessing MVD have included Chalkey point counting and multiparametric computerized image-analysis systems, which may have advantages over manual vessel counting, but are more time-consuming (31).

Some investigators have suggested that assessing intratumoral MVD or other markers of endothelial cell proliferation, such as endoglin (34), with serial tumor biopsies over time may offer an insight into the biological activity of a given AI. Unfortunately, the ability to obtain serial tumor biopsies in cancer patients has been difficult. Few tumor types manifest metastatic disease in easily accessible sites. Exceptions include malignant melanoma and Kaposi's sarcoma (KS), which often present with multiple skin lesions. Although there is much enthusiasm for evaluating AIs in patients with HIV-related KS, this disease entity may not behave in the same way as other, more typical, epithelial tumor types. The requirement for serial biopsies has been incorporated into other clinical trials, including those that attempt to determine the development of multidrug resistance (MDR) gene expression over time, as patients are treated with a particular cytotoxic chemo therapy agent. Many of these trials encountered difficulties obtaining serial biopsies, because patients refused, biopsy sites were either inaccessible or associated with significant biopsy-related morbidity, or patients were too ill to undergo the procedure.

An equally important issue, as it relates to the assessment of an AI with serial biopsies for intratumoral MVD, is whether changes in these indices actually reflect the biologic activity of the AI. If serial tumor biopsies could be easily obtained, a more informative measure of AI activity may be evaluating changes in markers for endothelial cell proliferation, apoptosis, or angiogenic peptide, or integrin expression within the tumor. A potential problem inherent in this strategy is sampling error from one biopsy to another. A clinical setting in which it may be feasible to assess these types of markers is a pilot study in which patients must undergo a biopsy to confirm the diagnosis of cancer, prior to definitive surgery. In the interval prior to definitive surgery, patients could be enrolled on a study to assess the short-term biologic effects of an AI. Such study designs have been utilized successfully, including a recent report describing the effects of a new pure antiestrogen, ICI 182780, in patients with primary breast cancer (35). DeFriend et al. (35) assessed the pharmacokinetics, toxicity, and short-term biologic activity of ICI 182, 780 in 56 patients with primary breast cancer, who received daily intramuscular injections for 7 d. Following breast surgery, tumors were assessed for changes in the proliferation marker Ki67, PR, and ER expression. Patients with operable lung cancer, colorectal cancer, and sarcomas, as well as other tumor types, may be suitable candidates for this type of trial design, which may provide insight into the biologic activity of a particular AI.

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  • paladin
    What is intratumoral microvascular density?
    7 years ago

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