Microvessel Density as a Prognostic Device for Cellular Pathology in Oncology - Assignment Example

Microvessel Density as a Prognostic device for Cellular Pathology in Oncology Introduction An integral component of oncology must be devoted to the study of tumor growth and the ways in which neoplasms sustain themselves. It is not enough to simply investigate chemical and drug-based solutions to cancer without understanding the ways in which various tumors propagate and maintain themselves within the body. The tumor no longer serves a constructive purpose within the larger body, and no longer responds to apoptosis signals that would have limited its growth, characterized by hyper active expansion throughout their respective tissues and spreading to the rest of the body. Oncologists need a variety of tools to fight a variety of cancers originating from different body tissues through different mutations arising from different mechanisms, whether chemical, viral induced, or the random activation of oncogenes. The bewildering variety of cancers insurers that different tumors are not guaranteed to respond the same way to all treatment types, creating the necessity for a wide range of options. Moreover, certain treatments may be helpful, but not fully curative and must be supplemented with other tactics. Doctors need as many weapons in their arsenal as possible – and in order to develop these new tools it is essential to gather data concerning the life of a cancer cell. Specific to this investigation is the question of how cancer feeds itself. This must be accomplished through tapping into the normal nutritional resources of all other cells, those nutrients traveling by way of the bloodstream, but as cancer grows its needs increase. And as a tumor far outstrips the healthy boundaries of its respective tissue type it must find a way to obtain far more sustenance. This is accomplished through the generation of new capillary blood vessels in a process known as angiogenesis. Naturally, it is conventional wisdom among oncologists that this represents a valid and vital means of attack. Stop the tumor from growing the new blood vessels it needs and you will obviously stop it. Hence the motivation for many years to develop a range of clinical tactics intended to impede angiogenesis. But in any research initiative for the development of new pharmaceuticals it is essential to provide unambiguous evidence of measurable practical benefit compared to older drugs, or a placebo. Therefore measurement standards are required to judge the effectiveness of anti-angiogenic therapy pertaining to cancer treatments. This article is intended to address the question of micro vessel density. By studying the density of blood vessels resulting from tumor angiogenesis, how will this factor allow us to predict the prognosis of the cancer in general? What curative challenges are inherent based upon what level of micro vessel density within a given tumor? This investigation will document research concerning the predictive value of micro vessel density as a diagnostic tool, and also characterize patterns in cancer research going back decades in order to establish the foundations for modern research. The rich body of cancer research extends through most of the 20th century, and it is necessary to examine older assumptions in light of more modern discoveries. To that end, historically articles will be referenced in addition to more recent ones. Literature review Current directions in tumor research operate under the assumption that the study of angiogenesis will in fact become an integral diagnostic and prognostic tool for systematic tumor evaluation (Nico et al. 2008). Nico in particular describes the issue of micro vessel or microvascular density as being the gold standard with respect to the morphological assessment of angiogenesis in human tumors. This factor has been suspected for many decades, with historical studies dating back to 1972 which identify a grading system for angiogenesis to give oncologists improve the diagnostic tools needed to assess various cancers (Brem et al. 1972). It is also worthwhile to provide a description of the physiological underpinnings of the angiogenesis process, in order to attain insight concerning the possibilities of future research and the evidence guiding current investigations. In healthy bodily tissues, their normally exists a balance between matrix metalloproteinases and tissue embedded inhibitors of metalloproteinases. This equilibrium is disrupted in the case of active angiogenesis. The matrix metalloproteinases (MMP) increases with respect to its inhibitor, tissue inhibitors of metalloproteinases (TIMP). As the enzyme surpasses its inhibitor, new blood vessels begin to invade surrounding tissues to provide sustenance for renegade cell clusters that may become malignant (Miller & Sledge, 2003). In addition to describing the physiological mechanisms, It is also possible to make generalizations concerning high levels of angiogenesis and specific types of carcinomas, specifically cancers of the prostate or the breasts – characterized by high levels of micro vessel formation. Considerable research has been devoted to the characterization of breast cancer, with confirmation of the importance and predictive power of angiogenesis in the tumorigenesis process. There is considerable support for the utility of micro vessel density analysis as a predictive methodology for these tumors, with historic evidence that angiogenesis precedes the malignant transformation of mammary cells into fully cancerous carcinomas arising from relatively benign papillomas. Much more work still needs to be done concerning the universal mechanism to categorize the total angiogenic function of the tumor in question. Theories exist concerning the relative micro vessel density of the various tumors under various circumstances and to what extent this density may characterize different cancer types, but an absolute scale remains controversial. In some cases, the vast and diverse city of cancer treatment methods including antibodies and methods for antigen extraction, as well as micro vessel density estimations may serve to complicate the overall field of cancer research – posing a challenge for the researcher seeking to organize all known findings on a particular aspect of cancer biology/pathology. Scoring systems do exist, such as that proposed by Brem et al. as described above, but methods vary. Brem employed in addition to micro vessel density quantities of endothelial cell nuclei as well as psychological factors to determine a rank order for angiogenesis when working with human brain tumors. There is room for additional research concerning a consistent scale applicable to all tumors. Another older study compared the angiogenesis of skin melanomas, and determined that skin cancers possess a vascular density twice that of cases where malignancy was not present (Srivastava et al. 1988). There is little doubt that higher rates of angiogenesis do indeed correlate with the emergence of certain tumors, but at present the connection may not be absolute: breast cancer studies indicate that lesions with the highest amount of micro vessel density do carry the greatest risk of breast cancer, but it is not entirely certain whether there is an absolute threshold of density beyond which carcinomas must occur. Guinebretiere et al. (1994) and Jensen et al. (1982) in both cases identified the abnormal proliferation of new capillary vessels as preceding the growth of the tumor, but doubt exists concerning exactly when or if a tumor will appear and become malignant based on a particular observation of angiogenesis. Correlations do exist between the formation of blood vessels and the emergence of a malignant tumor, but challenges still exist regarding classification and quantification. While it is not clear if there is a definitive threshold of angiogenesis, the observation that micro vessel growth tends to precede the development of a tumor led to further rounds of therapeutic experimentation indicating that transfection of cancerous tissue with factors antagonistic to angiogenesis decrease the probability of further growth and malignancy (Miller & Sledge, 2003). This is compelling evidence describing the importance of micro vessel growth and density in carcinomas. This progression is also tracked biochemically, the aforementioned metalloproteinase enzymes begin to increase in expression as of growth proceeds in stages from a benign mass to a fully malignant tumor. But it is well-known that not every irregular growth or mass becomes a life-threatening carcinoma, the tumorigenesis process includes an element of randomness. Some mutations leading to angiogenesis and irregular growth may exist in certain tissues but without becoming fully invasive. But it is among these invasive growths that malignancy can emerge in the case of a particular mutation of a particular oncogene. As cells continuously grow and divide in the millions over many years, each replication event creates a probability that the right (or wrong) mutation will occur in cells that already carry some growth irregularities. If this chain of mutations is not counteracted by surgical or curative methodologies, then once the genetics are in place the tumor will begin to proliferate rapidly, outstripping other cell types with more modest growth rates. This is often referred to as angiogenic switch (Miller & Sledge, 2003). Micro vessel density is certainly a valid indicator, but other studies indicate a far more complex picture with respect to the role of this factor in the lifecycle of cancer. In addition to a correlation between micro vessel density and a high probability of the emergence of a malignant tumor, correlations also exist between the density of these blood vessels and the recurrence of a tumor. But general agreement does not exist, and certitude is not possible in all cases. The emergence is dependent upon the probability of a chain of mutations which need not occur in all instances. There are also areas of less certainty that may correlate with micro vessel density: it may be possible to correlate the extent of a tumors invasiveness, in addition to decreased survival of the patient based on density. Taken together, this single factor may be the most vital external determinant, because the presence of these blood vessels and the ability of the cancerous tissue to generate new ones establishes the physical underpinnings necessary for carcinogenesis to sustain itself. Therefore, genetic factors concerning which oncogene may or may not mutate are arguably secondary, because cancer cells must have a reliable system of nutrition before any malignancy is possible. But how much they need is debatable, as other findings in this analysis will attest. In addition to the challenges of probability, additional research is needed concerning standardization of a precise counting procedure. The tangle of tiny capillaries supporting an irregular tumor are difficult to accurately trace in the best of circumstances, and attempts to quantify them are often subjective, especially in cases where a single vessel is twisting circuitously throughout a large section of tissue, where it might be isolated and counted multiple times. This is a significant obstacle with respect to the predictive power of micro vessel density – if micro vessels cannot be accurately characterized. Modern solutions to these historical problems often involve immunohistochemical staining in order to reduce subjectivity in the determination of blood vessel counts (Nico, 2008). Also relevant to the question of the predictive power of micro vessel density is the need to develop standards with respect to various quantitative processes. Historically methods employed the Chalkley system which uses a magnification grid to study a series of apparent hotspots within pre-stained micro vessel samples. But other researchers employ a more arbitrary selection of locations under a microscope (Oh et al. 2001), which might seem viable under the expectation that tumors themselves are irregular and random. But this method can be criticized due to the fact that while there is no symmetry to cancer in a general sense, an analysis of the entire affected area will reveal heterogenous variation in the size and growth areas of a particular tumor, arguably with corresponding micro vessel density. Challenges to the Density Theory In addition to probabilistic differences concerning whether and under what circumstances malignancy will occur, evidence exists of types of tumors that may metastasize in a manner independent of micro vessel density, or perhaps with an inverse correlation. The extent of micro vessel density before malignancy occurs does very, as stated previously in this analysis. While skin cancers may exhibit twice the degree of vascularity according to earlier historic studies, the vessel density in the case of lung cancer according to some studies was found to be just under 30% that of healthy lung tissue (29%) (Turner et al, 2000). While tumors require a blood supply, there are certain cases where the blood supply necessary is actually reduced compared with healthy tissues. Exact percentages can vary significantly. Therefore we should not reasonably expect any singular calculation of micro vessel density that is applicable to all tissues. But even decades ago, other studies existed casting doubt on a simplistic micro vessel density hypothesis. It is been presumed that the importance of angiogenesis would permit a definitive predictive matrix through an estimation of micro vessel density, and the specific longitudinal study relating to prostate cancer is highly relevant to the question (Rubin et al. 1999). This study occurred over the course of two years including 87 total patients undergoing treatment as well as outpatient therapy, with follow-up times on average of 36 months. With this specific type of cancer, it is common to track levels of prostate specific antigen as a way to determine the likelihood of malignancy. But agreement did not evidently exist between this method and estimations of micro vessel density. Rubin and colleagues agree that it is possible to accurately count vessel density, but could not correlate it to the emergence or recurrence of prostate cancer as a reliable prognostic indicator. But more recent studies cloud the issue even further. Independent researchers working within the same overall body tissue can arrive at different conclusions concerning the importance of micro vessel density for tumors arising from the same source. Another comprehensive longitudinal study comprising a meta-analysis of 87 published studies was conducted as a way to harmonize diverse conclusions (Uzzan et al. 2004). While data has been presented during this analysis concerning lung cancer for example, other researchers have reached seemingly opposite conclusions – in that enhanced angiogenesis may be essential as a predictive indicator for lung cancer, but the possibility exists that this prognostic utility is limited only to small cell lung cancer (Meert, 2002). With respect to breast cancer an overall aggregate of different studies, sometimes reaching opposite conclusions tentatively supports the idea of a modest or loose correlation between micro vessel density and breast cancer (Gasparini, 2001). Attempts to explain these discrepancies reveal underlying complexities with respect to the physiology of tumors. While a growing tumor must secure its energy supply through angiogenesis, individual tumor cells themselves exhibit diminished consumption rates of oxygen compared with healthy tissues. And when these blood vessels do form, as a consequence of the irregularity of tumors new micro vessels will differ in the amount of oxygen and nutrients they are able to furnish to individual cancerous cells. The randomness of these structures may lead to inconsistent blood flow. Therefore it is reasonable to hypothesize that not all blood vessels are created equal by way of angiogenesis. As a consequence of decreased oxygenation, many tumor cells can better tolerate oxygen deprivation. The random web of inconsistently functional micro vessels challenges are attempts to accurately quantify them (Hickley & Simon, 2006). There are also variations in angiogenesis that introduce more exceptions to the rule with respect to the ability of micro vessel density to serve as a predictive system. Oxygen and nutrition are required for a tumor to become malignant, but the extent of micro vessel density does not appear to correlate with the aggressive tendrils use by a solid tumor to infiltrate surrounding tissues. A tumor must send invading extensions of itself into surrounding tissues in order to grow, but these infiltrations themselves are apparently not dependent on pre-existing micro vessels (Korkolopoulou et al. 2001). Hence raising the question of probabilities again; there are certain things a tumor needs in order to grow, but it will not necessarily become malignant if these factors exist – and if it will become malignant it is difficult to predict exactly when this might occur. A tumor can proliferate to the surrounding tissues, and in certain tissues increase micro vessel density is necessary, but the fact that it exists does not necessarily indicate that malignancy is in progress. Conclusions There exists a wide range of possible tumors in most body tissues, some resulting from exposure to chemical mutagens, some induced through the action of viruses, and others are simply the consequence of time and chance. A detailed study indicates that in parallel to the fact that cancers themselves have such varied pedigrees, it is unlikely that there will be a simplistic diagnostic or prognostic solution universally applicable in all cases, for all tumors. The most reasonable assessment of the current state of knowledge is that different tools have predictive value for different pathologies. Micro vessel density does appear to be highly relevant in the case of certain obviously solid tumors (for leukemia the discussion is irrelevant) such as breast cancer, and it is important in certain high-grade tumors, but not necessarily the case for the invasive extensions of a malignant tumor, and it may not apply in low-grade tumors. And as shown above in the Turner study, not all lung cancers will conform to this model. With respect to grade of cancer, this is in reference to the extent of de-differentiation, or reversion from the normal differentiated state of healthy tissues as a result of anaplasia, which is a common outcome of malignancy (Gelehrter & Grech, 2013). It is quite possible to find conflicting outcomes regarding the role of micro vessels concerning the same body tissues. The cancer itself is not a singular phenomenon with completely identical causes and structures – it would be far easier to cure in such a case. With the possibility of different sorts of tumors developing in the same body tissue that may or may not be subject to the same treatment modalities, generalizations across the spectrum of oncology research are unwise at present. While correlations are imperfect between micro vessel density and certain forms of tumors, it would be wrong to say that the technique is useless. Anymore than it would be wrong to say that radiation is useless because it may not be able to affect certain highly diffuse cancers or leukemias. With such a wide variety of possible cancer related phenomena and initiating causative factors, the most logical strategy is to employ a diversity of tools. There is no singular physical treatment that is applicable for all tumors in all cases, nor then can there be a singular, universal prognostic analytical tool. Some of the information described during the course of this analysis allows for certain hypotheses which could be confirmed or refuted through additional research: the possibility exists that high-grade tumors have altered their metabolism to the extent that they require less oxygen and nutrition, and that this explains startlingly low results with respect to vessel density and angiogenesis for some lung cancers as documented in the Turner study. Since these cells are not performing any specific metabolic function useful for the body beyond their own survival and proliferation, it is reasonable to suspect that they optimize their resources simply for the purpose of multiplication. A competitive selection process could exist amongst the cells from which certain tumors arise whereby the most energetically efficient replicators crowd out healthy cells and less aggressive tumors, accounting for the growth of some carcinomas able to grow with far less oxygen than normal. Another potential hypothesis also subject to further testing could be the fact that tumors in the lungs are already receiving considerable oxygen, and require less from blood. Even if this were possible, the healthy cells within the lungs should also derive this benefit, so in any event high-grade tumors are likely to contain genetic factors that optimize them for pure proliferation beyond that of normal cells. This and other possibilities must be evaluated through a variety of tools, not a simple reliance on any singular strategy. References Brem, S.S., Gullino, P.M., Medina, D. 1977. Angiogenesis: A marker for neoplastic transformation of mammary papillary hyperplasia. Science 195:880-882, 1977 Gasparini, G. Clinical significance of determination of surrogate markers of angiogenesis in breast cancer. Crit Rev Oncol Hematol, 37: 97-114, 2001. Gelehrter, T.D., Grech, A., 2013.Patients and Populations: Medical Genetics. Open.Michigan.edu. Creative Commons Attribution-NonCommercial-ShareAlike license. Guinebretiere, J.M., Le Monique, G., Gavoille, A., et al: 1994. Angiogenesis and risk of breast cancer in women with fibrocystic disease. J Natl Cancer Inst 86:635-636, 1994. Hickey M.M. and Simon M.C. (2006). Regulation of angiogenesis by hypoxia and hypoxia-inducible factors. Curr. Top. Dev. Biol. 76, 217-257. Jensen, H.M., Chen, I., DeVault, M.R., et al: 1982. Angiogenesis induced by “normal” human breast tissue: A probable marker for precancer. Science 218:293-295, 1982 Korkolopoulou P., Apostolidou E., Pavlopoulos P.M., Kavantzas N., Vyniou N., Thymara I., Terpos E., Patsouris E., Yataganas X. and Davaris P. (2001). Prognostic evaluation of the microvascular network in myelodysplastic syndromes. Leukemia 15, 1369-1376 Meert, A.P., Paesmans, M., Martin, B., et al. 2002. The role of microvessel density on the survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer, 87: 694-701, 2002. Miller, K., Sledge, G.W. 2003. Dimming the blood tide: Angiogenesis, antiangiogenic therapy and breast cancer, in Nabholtz JM (ed): Breast Cancer Management Application of Clinical and Translational Evidence to Patient Care (ed 2nd). Philadelphia, PA, Lippincott Williams & Wilkins, 2003, pp 287-308 Nico, B., Benagiano, V., Mangieri, D., Maruotti, N., Vacca, A., Ribatti, D. 2008. Evaluation of microvascular density in tumors: pro and contra. Histol Histopathol (2008) 23: 601-607. Oh J., Takahashi R., Kondo S., Mizoguchi A., Adachi E., Sasahara, R.M., Nishimura S., Imamura Y., Kitayama H., Alexander D.B., Ide Seiki Rubin. M.A., Buyyounouski, M., Bagiella, E., Sharir, S., Neugut, A., Benson, M., de la Taille, A., Katz, A.E., Olsson, C.A., Ennis, R.D. 1999. Microvessel density in prostate cancer: lack of correlation with tumor grade, pathologic stage, and clinical outcome. Urology. 1999 Mar;53(3):542-7. Srivastava A., Laidler P., Davies R., Horgan K. and Hughes L.E. (1988). Srivastava A., Laidler P., Davies R., Horgan K. and Hughes L.E. (1988). Turner H.E., Nagy Z., Gatter K.C., Esiri M.M., Harris A.L. and Wass J.A.(2000). Angiogenesis in pituitary adenomas and the normal pituitary gland. J. Clin. Endocrinol. Metab. 85, 1159-1162. Uzzan, B., Nicolas, P., Michel Cucherat, M., Perret, G.Y. 2004. Microvessel Density as a Prognostic Factor in Women with Breast Cancer A Systematic Review of the Literature and Meta-Analysis. doi: 10.1158/0008-5472.CAN-03-1957 Cancer Res May 1, 2004 64; 2941 Read More