Abstract
Tumors may be either benign or malignant, where benign tumors may be precursors of malignant tumors. The most significant difference between benign and malignant tumors is that the malignant tumors have metastatic potential, whereas benign tumors do not metastasize. However, any benign or malignant tumor may cause death if inappropriately located. Characteristic differences between benign and malignant tumors are summarized. Below, different benign and malignant tumors are exemplified.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
3.1 Introduction
This text is intended as an overview of cancer pathology with particular reference to classification, tumorigenesis, microscopic features, sampling, and diagnostic techniques for ocular cancer.
3.2 Classification of Neoplasia
Tumors may be either benign or malignant, where benign tumors may be precursors to malignant tumors. The most significant difference between benign and malignant tumors is that the malignant tumors have metastatic potential, whereas benign tumors do not metastasize. However, any benign or malignant tumor may cause death if inappropriately located. Characteristic differences between benign and malignant tumors are summarized (Table 3.1). Below, different benign and malignant tumors are exemplified.
3.2.1 Benign Tumors
Benign tumors are usually labeled by the suffix -oma. Some exceptions tend to cause confusion; lymphoma and melanoma are by definition malignant, irrespective of the suffix -oma. To emphasize this, terms like malignant lymphoma and malignant melanoma are sometimes used:
-
Adenoma is composed of cells originating from glandular epithelium.
-
Hamartoma is composed of physiologic cells originating at the affected site.
-
Choristoma is composed of cells not normally occurring at the affected site, but otherwise histologically physiologic.
-
Teratoma is composed of pluripotent cells forming different types of tissue originating from one or more of the three germ cell layers. A teratoma may be either benign or malignant.
3.2.2 Malignant Tumors
-
Carcinoma is a neoplasm of epithelial origin. For example, an adenocarcinoma of the lacrimal gland is a cancer derived from the glandular epithelium of the lacrimal gland.
-
Sarcoma is derived from mesenchymal tissue.
-
Blastoma is a malignant tumor of embryonic origin. For example, retinoblastoma is derived from retinoblasts in the developing retina.
-
Leukemia is a malignancy of blood cells that arises from the bone marrow precursor cells and is present in the peripheral blood.
-
Lymphoma is a malignancy derived from lymph nodes, but may occasionally be present in other organs such as the lacrimal gland or in peripheral blood.
-
Melanoma is a malignant tumor that originates from melanocytes, i.e., cells containing intracytoplasmic pigment lodged in specific organelles, melanosomes. These cells appear in the skin, uvea, conjunctiva, and a variety of other tissues.
3.3 Tumorigenesis
Tumorigenesis is a multistep process in which normal cells progressively evolve to a neoplastic state. Advances in techniques for studying cancer genetics have revolutionized our knowledge of tumorigenesis [1]. The rapidly accumulating information on the genetic and epigenetic constitution of malignancies has made it possible to tailor novel therapeutic agents, several of which are in clinical use. Hanahan et al. structured a succession of “hallmarks” of tumor cells which mark the steps of tumorigenesis [1]. These hallmarks include genomic instability and mutations, evading immune destruction, proliferative signaling and reprogramming energy metabolism, resisting growth suppressors, escaping cell death, replicative immortality, angiogenesis, invasion and metastasis, and the tumor microenvironment. The hallmarks are briefly outlined below; the genes involved in tumorigenesis are discussed in greater detail elsewhere (Chap. 6).
3.3.1 Genomic Instability and Mutations
Believed to underlie many of the hallmark capabilities in neoplastic cells, genomic instability generates random mutations including chromosomal rearrangements (Fig. 3.1). Tumors progress by stepwise accumulation of enabling genetic mutations. Random mutations occur in genomic regions that drive malignant progression. Non-tumorigenic regions may also harbor “passenger” mutations that are not pathogenic but may serve as biomarkers [2]. Recurrent genetic aberrations and mutations across several different tumor types indicate that some genetic regions are important drivers of tumorigenesis [3]. The recent application of deep sequencing of entire cancer cell genomes will increase our knowledge of these apparently random mutations [4]. Studies have shown that mutations of telomerase and telomeres are required to achieve endless replication and survival [5]. However, recent evidence suggests that cells that survive the telomere erosion enter breakage-fusion-bridge cycles with resulting gross genetic aberrations. Tumor cells with these complex genetic alterations will have an accelerated acquisition of mutations and rapidly progress to more malignant states [6].
3.3.2 Evading Immune Destruction
The immune system plays an important role in eliminating both micrometastases and late stage tumors [1]. Studies on mouse models have revealed that deficiencies of NK and T cells result in a higher risk of developing cancer, which suggests that both the adaptive and innate immune systems serve as barriers to tumor progression [7, 8]. Tumor cells must therefore be able to evade immunological killing in order to thrive. This can be achieved, e.g., by altering immunological reactions by secreting immunosuppressive factors such as TGF-β [9].
3.3.3 Proliferative Signaling and Reprogramming Energy Metabolism
Proliferative signaling has been recognized as one of the earliest and most important steps in tumorigenesis [1]. It is mediated in large by growth factor ligands that bind to cell-surface receptors (frequently tyrosine kinase domains), which mediate proliferative signals, such as progression through the cell cycle, growth, survival, and energy metabolism [1]. By altering the proliferative signaling network, neoplastic cells become independent of their environment and are placed in a continuous state of “on.” The genes involved in growth signaling are referred to as oncogenes. Recently, new light has been shed on the adjustments of energy metabolism to suit the rapid growth of cancer cells [1]. The energy metabolism of cancer cells has been demonstrated to be different compared to normal cells; by using aerobic glycolysis tumor cells can increase their uptake and utilization of glucose, which has been documented in many tumor types and is utilized to visualize tumor dissemination in PET-scan examination [10].
3.3.4 Resisting Growth Suppressors
Apart from activating proliferation, tumor cells must also be able to avoid signaling pathways that negatively regulate cell proliferation. The genes controlling progression in the cell cycle and inhibitory signaling are commonly referred to as tumor suppressor genes. One of the most common suppressor genes is the RB1 gene. This gene is mutated in a wide range of tumors [11]. Individuals with germline mutations of RB1 suffer a great risk of developing bilateral retinoblastoma at young age, as well as several other tumor types. In normal cells, cell-to-cell contact mediates suppression of growth [1]. If normal cells lose the cell-to-cell contact, they undergo programmed cell death. This inhibitory signal is often lost in tumor cells. A set of cell-surface adhesion molecules, most notably the cadherins (E-cadherin and N-cadherin), are commonly altered in tumor cells enabling the tumor cell to let go and then reattach, thus serving as an important step in metastatic spread [12, 13].
3.3.5 Escaping Cell Death
Apoptosis is triggered by, e.g., environmental stress, elevated levels of oncogene signaling, and loss of attachment to other cells and functions as a guardian against malignant genetic change [14]. By escaping programmed cell death, tumor cells manage to survive even though they harbor multiple genetic changes.
3.3.6 Replicative Immortality
Normal cells are only able to replicate a limited number of times before they enter either senescence or cell death. Telomeres and telomerase protect the ends of chromosomes and are intimately involved in replicative immortality [1]. While telomerase is barely expressed in normal cells, its overexpression in malignancies allows the cells to escape destruction [4, 15].
3.3.7 Angiogenesis
Tumors must acquire new vasculature by angiogenesis to be able to grow beyond a size of approximately 2 mm2 (Chap. 4).
3.3.8 Invasion and Metastasis
Tumor metastases account for approximately 90 % of tumor-related death [16]. By pinpointing the processes underlying metastasis, greater understanding and treatment options will emerge [17]. The metastatic process is thought to start with individual tumor cells dislodging from the primary tumor and spreading by blood or lymphatic vessels. The timing of tumor dissemination remains a subject of debate. There are two major models: the linear progression model where a cell acquires a set of characteristics through stepwise alteration before dissemination and the parallel progression model where cells that are not yet fully neoplastic are circulating, suggesting that they are disseminated from an early malignant lesion [18, 19]. The invasion-metastasis cascade is a complex, multistep process where tumor cells must be able to invade locally through the extracellular matrix and stromal cell layers. The precisely organized architecture of surrounding normal epithelium serves as an effective barrier, which is overcome by invading tumor cells when the metastatic process starts [17]. The matrix metalloproteinases secreted by macrophages at the tumor periphery contribute to the loss of the basement membrane by proteolysis, which facilitates invasion of the stromal compartment [17, 20]. Invading cells must also become motile to escape the primary tumor; this is achieved by alterations in cell-surface proteins that promote migration. Alteration of the cytoskeleton allows for movement along the extracellular matrix and surface of other cells. Further, the Ras family of GTPases alters actin and myosin activity, which promotes movement [1].
After leaving the primary tumor and invading the stroma, the tumor cells must intravasate into blood or lymph vessels. Intravasation into blood vessels is enabled because malignant blood vessels have insufficient pericyte coverage and the interaction is weak between adjacent endothelial cells [17]. Acquiring an intrinsic vasculature is important for primary tumors in order to metastasize and for metastases to grow beyond a certain size. Indirect evidence for this has been obtained in uveal melanoma (and several other tumors) as tumor vessel counts have been associated with a poor prognosis [21]. Following intravasation, the tumor cells must survive the detachment from the supporting tumor matrix, the hemodynamic forces in the circulation, as well as the hostile immune system. The process of extravasation begins when the cell attaches to the vessel wall in the target tissue. This is achieved either by a tumor forming in the vessel wall, which eventually ruptures the vessel wall, or by penetrating the endothelial cells and pericyte layers and thereby establishing micrometastasis (Box 3.1) [22]. Tumors originating within the eye undergo hematogenous dissemination, because there is no lymphatic drainage. Tumors originating in the orbit or eyelids may undergo either hematogenous or lymphatic spread, depending on the tumor type.
Little is known about the predilection for particular metastatic targets, but two major theories have emerged: the mechanistic theory where tumor cells arrest within capillary beds due to size restrictions of the capillary vessels. The other theory describes receptor-ligand binding between tumor cells and capillaries, also known as the “seed and soil” theory: the provision of a fertile environment in which compatible tumor cells can grow [23]. Most likely the combination of both theories is true for the majority of metastatic malignancies. Some microenvironments seem to be more hospitable than others, exemplified by preferential dissemination by a wide range of different tumor types to the liver, bone marrow, and lung tissue. Extravasation of tumor cells is more challenging than intravasation since intravasation occurs at the primary tumor site where the vasculature is already quite leaky and therefore easy to traverse [17]. After intravasation the cancer cells must be able to adapt to a very different environment from that of the primary tumor. The process of metastasis is very inefficient. Indeed, it has been suggested that only <0.01 % of tumor cells that enter the circulation go through the metastatic process to establish clinical metastasis [24]. Even if the tumor cells initially survive in the new microenvironment, it is not certain that they will grow rapidly. On the contrary, most micrometastasis seems to go through a state of dormancy. This may be because of incompatibilities with the foreign environment; it may also be that the cells proliferate, though a net increase does not occur because of the counteracting effects of a high apoptotic rate [17]. An explanation of the high cell turnover and dormancy may be the failure to form new vessels [24].
3.3.9 The Tumor Microenvironment
Tumors are rarely isolated masses of homogenous proliferating cells, but rather a makeup of different tumor subpopulations as well as tumor-associated stroma, normal tissue, and infiltrating lymphocytes. Recent studies have shed light on the importance of recruitment of normal cells, which play a distinct role in the development of neoplasms, and also have been implicated in processes such as drug resistance [25]. The stroma surrounding the tumor is frequently reactive and shares similar upregulated pathways, e.g., chronic inflammation or wound healing tissue [26]. The tumor-associated stroma is induced by the neoplasm, and in turn, the stromal cells may increase the aggressive behavior of the tumor by releasing growth stimulating factors [17, 27]. Other incidents in the tumor microenvironment may increase the reactivity of the tumor surrounding stroma further. As an example, necrotic cell death releases pro-inflammatory signals into the surrounding microenvironment, which recruits inflammatory cells [26]. These cells may promote angiogenesis, cancer cell proliferation, and invasiveness [28]. Necrosis may therefore act tumor promoting; indeed tumors with necrosis are associated with worse clinical prognosis.
Solid tumors constitute a mixture of different tumor clones at different stages of development, which lead to genetic heterogeneity [29]. The existence of cancer stem cells as an important composition of the proliferating neoplasm has been a source of ongoing discussion (Fig. 3.2). Cancer stem cells are defined by their ability to seed new tumors when inoculated in host mice [30]. They have been suggested as the culprits of acquired chemotherapy resistance as well as disease recurrence after successful debulking of primary disease where no residual disease can be detected [31].
Box 3.1: Steps in Metastatic Process
-
Tumor invasion of the vasculature or lymph vessels
-
Tumor cell survival in the circulation
-
Cellular extravasation
-
Establish a metastasis at a distant site
-
Acquiring an intrinsic vasculature
3.4 Microscopic Features of Neoplasia
Certain histopathologic features differentiate benign and malignant tumors from surrounding normal tissues. In general, the differences from the normal tissue are more marked in malignant tumors than in benign tumors.
3.4.1 Cellular Proliferation
Many malignant tumors feature a large number of dividing cells with abnormal mitotic patterns (Fig. 3.3a). Cell proliferation markers like proliferating cell nucleolar antigen (PCNA) and Ki-67 often reveal a larger proportion of proliferating cancer cells than detected by mitotic counts alone (Fig. 3.3b). A high mitotic index (mitotic count per unit of microscopic area) is often found in rapidly growing tumors although this is usually balanced by the presence of many apoptotic cells. Not all cancers show high cell proliferation rates; typically uveal melanoma features comparatively low counts, but nonetheless may metastasize. However, in many cancers, including uveal melanoma, a high cell proliferation rate is associated with poor prognosis [32, 33].
3.4.2 Cellular Pleomorphism
When tissue and cellular architecture is distorted, the tissue is classified as dysplastic. Epithelial dysplasia may be divided into mild, moderate, and severe dysplasia. Severe dysplasia is characterized by full thickness dysplasia with prominent cellular atypia and is synonymous with carcinoma in situ. It is debatable whether a slight or even moderate degree of dysplasia is precancerous, a condition inevitably leading to cancer. When tissue architecture is considerably distorted with individual cells showing a significant degree of variation in shape and size including abnormal nuclei sometimes featuring binucleate or multinucleate forms, this is referred to as pleomorphism at the cellular level. Cellular pleomorphism, including the extreme state when the tissue of origin is no longer recognizable (anaplasia), is a hallmark of cancer.
3.4.3 Cellular Differentiation
Typically, cancers recapitulate the architecture of the tissue of their origin to some extent. This recapitulation may closely resemble the original structure and such cancers are highly differentiated, whereas others are poorly differentiated or even anaplastic. Usually, poorly differentiated cancers carry a worse prognosis than cancers more closely mimicking the original tissue appearance. In retinoblastoma, the rosettes appearing in moderately and highly differentiated retinoblastoma are believed to be an attempt to recapitulate the original retinal structure (Fig. 3.4a). In uveal melanoma, the tumor spindle cell morphology resembles the original melanocytes, and the presence of less differentiated epithelioid cells is associated with an adverse outcome (Fig. 3.4b, c) [34].
3.4.4 Nuclear Cytoplasmic Ratio
Most neoplastic cells have a relatively large nucleus in relation to the amount of cytoplasm. However, this varies significantly with the type of neoplasia. Clear cell carcinoma of the kidney features large cells with abundant cytoplasm, whereas the retinoblastoma typically is composed of cells with relatively large nuclei and small amounts of cytoplasm.
3.4.5 Invasion of Surrounding Tissues
Tumor cells invade surrounding tissue by direct infiltration or by dissemination along blood or lymphatic vessels. In carcinoma, breakdown of the basement membrane and stromal invasion signify the progression of an in situ carcinoma to invasive carcinoma. Cancers with minimally invasive features are sometimes referred to as microinvasive.
Some malignant tumors show a particular affinity for spread along peripheral nerves extending a considerable distance away from the primary site (e.g., perineural growth in adenocystic carcinoma of the lacrimal gland). In some of these tumors, severe pain due to invasion or compression of sensory nerve fibers may be the first clinical presentation.
3.4.6 Tumor Infiltration by Normal Cells
In some malignant tumors, infiltration by macrophages or lymphocytes is a characteristic feature reflecting recruitment of the immune system as well as physiologic cells by neoplastic tissue. Macrophage infiltration in uveal melanoma is associated with a poor prognosis [35].
3.5 Tissue Sampling and Processing
3.5.1 Cytological Sampling
Sampling typically includes a number of individual cells disrupted from their original tissue. Diagnosis is therefore usually made on the morphological appearance of individual cells because the relationship to surrounding cells is lost. Cytological samples may be used for immunocytochemistry, which is conducted to characterize protein expression, and for auxiliary techniques such as flow cytometry. Two basic techniques are used for sampling.
3.5.1.1 Exfoliative Cytology
Exfoliative cytology involves sampling of cells that are dispersed in fluids (e.g., cerebrospinal fluid sampled by lumbar puncture) or forcibly removed by a spatula, brush, or some other instrument or filter paper. Cells may also be dislodged from a surface by a touch preparation, for example, imprint cytology for conjunctival tumors. The exfoliative sample is then spread on a glass slide and stained. Vitrectomy samples may be filtered though a membrane (e.g., Millipore filter), centrifugated in a pellet (cytospin preparation) or paraffin embedded as a cell block.
3.5.1.2 Aspiration Cytology
Aspiration cytology may be applied to palpable lesions, guided by ultrasound or computerized tomography imaging. Intraocular fine-needle aspiration biopsy (FNAB) is performed with needles between 21 and 25 gauges [36]. A pars plana approach guided by indirect ophthalmoscopy may be used, but clear cornea and transscleral routes have also been advocated [37–39]. The various techniques of intraocular biopsy are discussed in detail under uveal tumors. Local tumor spread using FNAB in loosely cohesive tumors is a concern. For this reason, FNAB should only be used with extreme caution and almost never in suspected cases of retinoblastoma. The requirements for tissue handling vary between laboratories; therefore, it is advisable to contact the local cytopathologist before sampling.
3.5.2 Histopathologic Sampling and Processing
Tissue is obtained by incisional or excisional biopsy of the lesion. Caution not to coagulate or otherwise maltreat the tissue sample is recommended. Incisional biopsies or core needle biopsies should be avoided in tumors prone to local recurrence, e.g., the pleomorphic adenoma of the lacrimal gland. In such tumors, primary complete excision or possibly diagnostic FNAB followed by complete excision is recommended. The optimal fixative for the surgical biopsy varies depending on the local setting and the technique used for histopathologic examination, but for most cases, formaldehyde is sufficient.
When biopsying tissues like the conjunctiva or iris, care should be taken to orientate the specimen and to make sure the tissue is maintained flat and does not curl. This can be achieved by attaching the tissue to a piece of filter paper and annotating the specimen mount before immersion in the fixative. Assessment of the surgical margins is pivotal in any excisional tumor biopsy. To facilitate this, the surgical margins may be marked by the pathologist before gross sectioning and paraffin embedding. Also, special techniques like Mohs technique using cryosectioning or modifications using vertical paraffin-embedded sections have been advocated for eyelid and skin tumors [40, 41]. Cryosectioning allows for a rapid assessment (within 30 min) of margins or malignancy and can be used as a preoperative procedure; however, paraffin sections allow a more reliable microscopic assessment. Specific guidelines for histopathology reports on cancer specimens from the eye and adnexa have been discussed elsewhere [42].
3.6 Diagnostic Techniques
Traditionally, cancer diagnosis was made using light microscopic examination, but recent advances in molecular diagnostics have created a completely new set of tools with which tumors may be more accurately diagnosed and better characterized. Some of these techniques are outlined below.
3.6.1 Light Microscopy
When processed for routine light microscopy, samples are usually fixed in formaldehyde and then embedded in paraffin. This allows for the cutting of 3–4 μm sections. Paraffin sections are usually routinely stained with hematoxylin and eosin, although this may differ depending on the local routine (Fig. 3.5a). Other stains like the periodic acid-Schiff dye preferentially stain mucopolysaccharides and glycogen and are appropriate for study of basement membrane material like the lens capsule.
3.6.2 Immunohistochemistry
This technique has rapidly evolved from a research tool to a diagnostic technique and has revolutionized diagnostic pathology. Several commercially available antibodies may be used in combination with routine fixatives like formaldehyde and staining may be enhanced by antigen retrieval techniques (Fig. 3.5b). Fixation over prolonged periods of time may cause reduced staining and the wary pathologist uses negative and positive controls.
3.6.3 Additional Techniques
Recent advances in molecular pathology have generated numerous techniques for the genetic and epigenetic study of ocular tumors. One of the most important laboratory techniques is the polymerase chain reaction (PCR). Several different types of PCR have been developed, including competitive or real-time PCR, which allows for sensitive assays of gene expression at the RNA level. Further, several experimental laboratory techniques have been translated into clinical use, e.g., flow cytometry in lymphoma and tissue imprints for gene rearrangements in rhabdomyosarcoma. In several cases, tissue needs to be submitted fresh, which requires close collaboration with the examining laboratory for optimal results. Microarrays have revolutionized our understanding of the tumor genome and transcriptome by making it possible to study thousands of genes in one experiment at a single gene resolution. Distinct cancer biomarkers and gene expression profiles have been identified through microarray studies. After vigorous evaluation, several assays have been developed and are now in clinical use. Two of the earliest assays developed include the MammaPrint® and Oncotype DX® assays [43, 44]. These assays predict prognosis and assess the likely benefit from treatment by analyzing signatures of multiple genes. In uveal melanoma, genome-wide expression profiling has identified two subsets of tumors: nonmetastasizing low-grade tumors and metastasizing high-grade tumors [45]. From these results, a 15-gene assay has been developed, which successfully separates the tumors into two distinct subgroups [12, 46]. Through fine-needle biopsies, the assay can be used to determine metastatic potential and patients can be selected for interventions like adjuvant therapies [47, 48]. Functional analysis of the genes involved in the high-grade profile has allowed identification of upregulated genes and pathways in uveal melanomas. This constitutes an important basis for novel strategies for early tumor identification and application of targeted therapies. Several antibodies have been investigated in ocular tumors, including aflibercept (VEGF-Trap) and ipilimumab (anti-CTLA4) [49, 50]. Ipilimumab is applied in routine clinical treatment, and several drugs are in various stages of clinical investigation (www.clinicaltrials.gov). In line with the findings in microarray studies, proteomics hold a similar promise and generate vast amount of data on protein expression.
Next generation sequencing of the whole genome has become a groundbreaking tool in the study of cancer cells. It is used for the characterization and identification of, e.g., DNA, RNA, exome, and transcriptome sequences of tumor cells. It enables identification of, e.g., copy number variants, sequence variants, mutations, and structural changes such as chromosomal translocations, and fusion genes. Various open source projects aim at collecting sequence variants and mutations critical in the development of human cancers. Public sharing of data has enabled inclusion in larger data sets for reanalysis and construction of databases of cancer profiles.
Described here are only a handful of the techniques developed for research and clinical study of tumors. In the near future many of the techniques used for experimental purposes will delineate central pathways in cancer cells with prognostic, diagnostic, and treatment implications in human cancer.
References
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Stratton MR. Exploring the genomes of cancer cells: progress and promise. Science. 2011;331:1553–8.
Korkola J, Gray JW. Breast cancer genomes – form and function. Curr Opin Genet Dev. 2010;20:4–14.
Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, Delaney A, Gelmon K, Guliany R, Senz J, Steidl C, Holt RA, Jones S, Sun M, Leung G, Moore R, Severson T, Taylor GA, Teschendorff AE, Tse K, Turashvili G, Varhol R, Warren RL, Watson P, Zhao Y, Caldas C, Huntsman D, Hirst M, Marra MA, Aparicio S. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009;461:809–13.
Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet. 2005;6:611–22.
Artandi SE, DePinho RA. Telomeres and telomerase in cancer. Carcinogenesis. 2010;31:9–18.
Teng MW, Swann JB, Koebel CM, Schreiber RD, Smyth MJ. Immune-mediated dormancy: an equilibrium with cancer. J Leukoc Biol. 2008;84:988–93.
Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, Massague J. Tumor self-seeding by circulating cancer cells. Cell. 2009;139:1315–26.
Shields JD, Kourtis IC, Tomei AA, Roberts JM, Swartz MA. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science. 2010;328:749–52.
Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 2009;23:537–48.
Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer. 2008;8:671–82.
Onken MD, Ehlers JP, Worley LA, Makita J, Yokota Y, Harbour JW. Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas. Cancer Res. 2006;66:4602–9.
Berx G, van Roy F. Involvement of members of the cadherin superfamily in cancer. Cold Spring cHarb Perspect Biol. 2009;1:a003129.
Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324–37.
Shay JW, Wright WE. Hayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol. 2000;1:72–6.
Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer. 2006;6:449–58.
Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275–92.
Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzikansky A, Ryan P, Balis UJ, Tompkins RG, Haber DA, Toner M. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature. 2007;450:1235–9.
Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmuller G, Klein CA. Systemic spread is an early step in breast cancer. Cancer Cell. 2008;13:58–68.
Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141:52–67.
Foss AJ, Alexander RA, Jefferies LW, Hungerford JL, Harris AL, Lightman S. Microvessel count predicts survival in uveal melanoma. Cancer Res. 1996;56:2900–3.
Al-Mehdi AB, Tozawa K, Fisher AB, Shientag L, Lee A, Muschel RJ. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med. 2000;6:100–2.
Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3:453–8.
Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–72.
Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500–4.
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.
Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, Wang YY, Meulle A, Salles B, Le Gonidec S, Garrido I, Escourrou G, Valet P, Muller C. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 2011;71:2455–65.
DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009;16:91–102.
Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie WR, Hicks J, Wigler M. Tumour evolution inferred by single-cell sequencing. Nature. 2011;472:90–4.
Cho RW, Clarke MF. Recent advances in cancer stem cells. Curr Opin Genet Dev. 2008;18:48–53.
Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29:4741–51.
Seregard S, Spangberg B, Juul C, Oskarsson M. Prognostic accuracy of the mean of the largest nucleoli, vascular patterns, and PC-10 in posterior uveal melanoma. Ophthalmology. 1998;105:485–91.
Seregard S, Oskarsson M, Spangberg B. PC-10 as a predictor of prognosis after antigen retrieval in posterior uveal melanoma. Invest Ophthalmol Vis Sci. 1996;37:1451–8.
Seregard S, Kock E. Prognostic indicators following enucleation for posterior uveal melanoma. A multivariate analysis of long-term survival with minimized loss to follow-up. Acta Ophthalmol Scand. 1995;73:340–4.
Makitie T, Summanen P, Tarkkanen A, Kivela T. Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci. 2001;42:1414–21.
Char DH, Kemlitz AE, Miller T. Intraocular biopsy. Ophthalmol Clin North Am. 2005;18:177–85, x.
Zorn KK, Bonome T, Gangi L, Chandramouli GV, Awtrey CS, Gardner GJ, Barrett JC, Boyd J, Birrer MJ. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005;11:6422–30.
Shields JA, Shields CL, Ehya H, Eagle Jr RC, De Potter P. Fine-needle aspiration biopsy of suspected intraocular tumors. The 1992 Urwick Lecture. Ophthalmology. 1993;100:1677–84.
Bechrakis NE, Foerster MH, Bornfeld N. Biopsy in indeterminate intraocular tumors. Ophthalmology. 2002;109:235–42.
Spencer JM, Nossa R, Tse DT, Sequeira M. Sebaceous carcinoma of the eyelid treated with Mohs micrographic surgery. J Am Acad Dermatol. 2001;44:1004–9.
Malhotra R, Chen C, Huilgol SC, Hill DC, Selva D. Mapped serial excision for periocular lentigo maligna and lentigo maligna melanoma. Ophthalmology. 2003;110:2011–8.
Folberg R, Salomao D, Grossniklaus HE, Proia AD, Rao NA, Cameron JD. Recommendations for the reporting of tissues removed as part of the surgical treatment of common malignancies of the eye and its adnexa. Am J Surg Pathol. 2003;27:999–1004.
van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530–6.
Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817–26.
Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64:7205–9.
Onken MD, Worley LA, Char DH, Augsburger JJ, Correa ZM, Nudleman E, Aaberg Jr TM, Altaweel MM, Bardenstein DS, Finger PT, Gallie BL, Harocopos GJ, Hovland PG, McGowan HD, Milman T, Mruthyunjaya P, Simpson ER, Smith ME, Wilson DJ, Wirostko WJ, Harbour JW. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012;119:1596–603.
Damato B, Dopierala JA, Coupland SE. Genotypic profiling of 452 choroidal melanomas with multiplex ligation-dependent probe amplification. Clin Cancer Res. 2010;16:6083–92.
Shields CL, Ganguly A, Bianciotto CG, Turaka K, Tavallali A, Shields JA. Prognosis of uveal melanoma in 500 cases using genetic testing of fine-needle aspiration biopsy specimens. Ophthalmology. 2011;118:396–401.
Danielli R, Ridolfi R, Chiarion-Sileni V, Queirolo P, Testori A, Plummer R, Boitano M, Calabro L, Rossi CD, Giacomo AM, Ferrucci PF, Ridolfi L, Altomonte M, Miracco C, Balestrazzi A, Maio M. Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy. Cancer Immunol Immunother. 2012;61:41–8.
Tarhini AA, Frankel P, Margolin KA, Christensen S, Ruel C, Shipe-Spotloe J, Gandara DR, Chen A, Kirkwood JM. Aflibercept (VEGF Trap) in inoperable stage III or stage iv melanoma of cutaneous or uveal origin. Clin Cancer Res. 2011;17:6574–81.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Bartuma, K., All-Ericsson, C., Seregard, S. (2014). Cancer Pathology. In: Singh, A., Damato, B. (eds) Clinical Ophthalmic Oncology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40489-4_3
Download citation
DOI: https://doi.org/10.1007/978-3-642-40489-4_3
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-40488-7
Online ISBN: 978-3-642-40489-4
eBook Packages: MedicineMedicine (R0)