Table of contents : 

Epidemiology Aetiology Pathogenesis Metastases Oncogenomics Morphology  Symptoms & signs Oncological emergencies Laboratory examinations tumor staging tumor grading

Experimental animal models Prevention Therapy  Prognosis Spontaneous tumour regression Specific organ cancers  Web resources Associations  Journals  Centers / Institutes / Organizations  News  Bibliography

• neoplasia : the progressive multiplication of cells under conditions that would not elicit, or would cause cessation of, multiplication of normal cells; the formation of a neoplasm / tumor : any new and abnormal growth; specifically a new growth of tissue in which the growth is uncontrolled and progressive
• Epidemiology
• Aetiology
• Pathogenesis
• Genetic bases (oncogenomics) : new mutations create subclones with selective advantages
• proto-oncogenes (c- : from cellular genome ; v- : from retroviral genome) : mutation in only one allele is enough for carcinogenesis
• growth factors
• p28^{c-simian sarcoma (Sis)} / PDGF-B [Simian sarcoma virus]
• p27^int2 / FGF3
• KGF / HST
• int1 / WNT1
• int3 / NOTCH1
• receptors for growth factors
• p170 HER1 / avian erythroblastosis 1 (ErbB1) / EGFR
• p185 HER2 / ErbB2 / Neu
• p170 c-FMS / CSF-1R
• p150 FLG / c-FMS2 / FGFR1
• K-SAM / p130 BEK / FGFR2
• p140 TRKA/C
• p250 c-ROS1 / v-ros UR2 sarcoma virus oncogene homolog 1 (avian)
• p145 c-KIT / CD117
• avian myelocytomatous leukemia (MIL)
• p120 RET / MEN2
• p195 c-MET / HGF-R
• MAS1
• EGFRs are frequently upregulated in breast cancers and glioblastomas : although gene amplification is one mechanism by which this might occur, oncongenic mutations in the CDC42 GTPase that cause it to stay in the active GTP-bound form (sequestering c-CBL and preventing it from degrading EGFR) might well constitute another^ref
• PPARb/d activation promotes growth and development of intestinal adenomas by activating anti-apoptotic pathways in intestinal epithelial cells^ref. Agonists in the later stages of development as drugs to treat dyslipidemia syndromes, obesity and atherosclerosis should be administered with caution, as they might increase the risk of cancer in individuals with familial adenomatous poliposis (FAP)
• PPARg signalling promotes the formation of mammary carcinomas in mice, but only in animals that are genetically predisposed to developing these tumours (e.g. mice that express the polyoma virus middle T antigen (PyV-MT))^ref. Activators of this receptor inhibit tumour development in rat models of mammary carcinoma, indicating that stimulating PPARg signalling might be a useful anticancer treatment. The WNT target geenes cyclin D1 and c-Myc are upregulated in mice expressing PyV-MT and constitutively active PPARg compared to mice expressing PyV-MT only. Increased expression wis also seen for b-catenin, a component of the Wnt pathway, and for the Wnt receptor frizzled homologue 4, whereas Wnt5a, a negative regulator of Wnt signalling, was downregulated. However, PPARg activators can suppress proliferation even in cells in which the receptor is not expressed and can cause increased tumour development in mouse models of colon cancer
• sonic hedgehog (SHH) and its receptor PTCH are expressed in 81% of gut-derived tumour cell lines (from esophageal, stomach, biliary, and pancreatic tumours).
• intracellular transductors
• G-proteins and their regulators
• monomeric G-proteins
• rat sarcoma (Ras) :
• 1964 : retroviral isolates were identified (also in 1967, 1974, and 1978)
• 1973 : Ha-MSV and Ki-MSV were found to contain rat cellular sequences
• 1979 : Ha-MSV cloned and p21 v-Ras was found to bind GTP
• 1981 : Ki-MSV was cloned
• 1982 : human oncogenes were found to be related to v-ras oncogenes. The first human transforming gens was cloned. The human HRAS oncogene was found to be activated by point mutation
• 1983 : neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) was identified. p21 RAS was found to be a GTPase. Ras oncogenes were identified in carcinogen-induced animal tumours. RAS was found to co-operate with MYC and E1A to transform primary cells
• 1984 : RAS was found to be activated by mitogenic factors
• 1987 : RAS-GAP was identified. RAS was shown to be frequently mutated in colon tumours. Ras transgenic mice were generated
• 1989 : RAS proteins were shown to be farnesylated
• 1990 : RAS-GEFs were identified
• 1993 : RAS was shown to interact with RAF
• 1994 : PI3K was shown to be a RAS effector
• 1995 : farnesyltransferase inhibitors (FTI) were found to block Ras-induced tumours in mice
During the 1970s, retroviral oncogenes were generically known as v-src. The realization that these oncogenes were distinct molecular entities led to the proposal that each oncogene should be named with a 3-letter acronym. In the case of Harvey and Kirsten strains, the chosen acronym was ras for rat sarcoma. The finding that v-h-ras and v-k-ras were derived from diffefret cellular loci led, for a brief period of time, to the use of the acronyms v-has for the oncongene present in Harvey-MSV, v-bas for the oncogene of BALB-MSV and v-kis for the Kirsten-MSV oncogene. Their cellular homologues c-has and c-bas corresponded to v-h-ras-1 (HRAS1 in humans) and c-kis to v-k-ras-2 (KRAS2 in humans). This nomenclature has not been used since 1984. Rodents and primates have 2 additional loci that are related to v-ras oncogenes, designated as Hras2 and Kras1 (HRAS2 and KRAS1 in humans). These loci represent processed pseudogenes. For simplicity, we will use the terms Hras (HRAS in humans) for Hras1 and Kras (KRAS in humans) for Kras2.
One of the key issues raised by mutational activation of RAS oncogenes in human tumours was whether they have an initiating - or at least causative - role in tumour development, or whether they are merely activated as a consequence of the genetic instability of malignant cells. As early as 1983, mutated Ras oncogenes were identified in experimental tumours of rodents that were exposed to chemical or physical carcinogens^{ref1, ref2, ref3}. Hras mutations were identified in benign papillomas of mice treateed with the 7,12-dimethylbenz[a]anthracene (DMBA) skin carcinogenesis protocol^ref. Evidence that Ras genes can be involved in the initiation of carcinogenesis was obtainedin 1985 when it was shown that Hras oncogenes that were activated in chemically induced mammary carcinomas od rats were activated by the type of mutations that is known to be caused by the initiating carcinogen^ref. Similar results were subsequently obtained using mouse hepatomas induced by various carcinogens of known mutagenic spectra^ref. The generation of tumours in mice harbouring Ras transgenes has leant further proof to the oncogenic properties of these genes in vivo. In 1987, several groups reported the induction of tumours by Ras oncogenes expressed under the control of various tissue-specific promoters.
• transgenic mice :
• MMTV-v-Hras : oncogenic Hras expression under the MMTV promoter) : mammary tumours, hyperplasia of the harderian gland and other malignancies^ref
• elastase-I-Hras (oncogenic Hras expression under the elastase-I-regulating elements) : rapid development (2 days) of neoplasia in the fetal exocrine pancreas^ref
• Tyr (Tet)-ras (oncogenic Hras under the control of the tyrosinase promoter and tetracycline regulatory sequences) : melanoma development; tumour regression after removal of activator^ref
• CCSP (Tet)-Kras G12D (Tet-regulated Kras oncogene drive by the Clara cell-secretory protein promoter) : adenocarcinomas of the lung and apoptotic regression after removal of inductor^ref
• gene-targeted mice
• Kras^-/- (Kras knockout) : embryonic lethality (E12-E14); fetal liver defects and anaemia^{ref1, ref2}
• Nras^-/- (Nras knockout) : viable, defective immune response and T-cell function^{ref1, ref2}
• Hras^-/- (Hras knockout) : no obvious phenotype; decreased tumour formation after carcinogenic treatments^{ref1, ref2}
• Kras^LA (oncogenic Kras G12D after spontaneous recombination) : "spontaneous" lung tumours, thymic lymphomas and skin papillomas^ref
• LSL-Kras G12D (Cre-inducible form of an oncogenic Kras knock-in) : tumours after activation of the ras oncogenic form with Cre recombinase^ref
Direct proof for the requirement of continuous Ras expression for tumour maintenance has been obtained using mice carrying inducible Ras trangenes^{ref1, ref2}. The advent of gene targeting in the embryonic stem cells has allowed the generation of more physiological tumour models in recent years^{ref1, ref2}. For instance, a conditional mutation in the endogenous mouse Kras locus that can be activated by ectopic expression of a Cre recombinase has bee engineered^ref. Infection of these mice with adenoCre vectors results in the efficient induction of lung tumours. Although this model does not completely mimics human tumorigenesis - for example, Kras becomes activated in a large number of cell - it represents a significant improvement in our quest for faithfully reproduce the human disease in a laboratory model.
• v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homolog (KRAS2) [Kirsten murine sarcoma virus]
Ras and Akt cooperate to alter the rate of recruitment to polysomes and synthesis of specific mRNAs : their oncogenic effects could, largely, be through translation, rather than transcription^ref.
N-ras and K-ras are mutated in many cancers, including 45% of multiple myelomas and > 50% of CMML cases. Constitutive activation of ras can mimic chronic stimulation by the corresponding lineage-specific growth factor.
Web resources : The Ras oncogene product by Frank R. Gorga, at Bridgewater State College
• heterotrimeric G-proteins
• Gsp (Gas)
• Gip (Gai2)
• Gep (Ga12)
• cyclins
• cyclin D1 (CCND1) / B-cell lymphoma 1 (BCL1) / Prad1 transcriptional activity is independent from CDK4 function and is mediated through C/EBPb
• cyclin D2 (CCND2)
• cyclin D3 (CCND3)
• antiapoptotic BCL2 family members
• B-cell CLL/lymphoma 2 (BCL2) gene was initially discovered by virtue of its involvement in the t(14; 18) (q32;q21) translocation^{ref1, ref2, ref3}. This chromosomal abnormality, resulting in production of high levels of bcl-2 protein, is observed in the majority of follicular non-Hodgkin’s lymphomas (NHLs) and in about 20% of diffuse large B-cell lymphomas^{ref1, ref2, ref3, ref4}. However, the expression of bcl-2 protein is not restricted to B-cell lymphomas bearing the t( 14; 18) translocation^ref. Indeed, immunohistochemical studies have shown that, beside follicular lymphomas^{ref1, ref2}, a broad spectrum of lymphoid malignancies including chronic lymphocytic leukemia, plasma cell dyscrasia, diffuse large B- and T-cell lymphomas^ref, as well as non-lymphoid tumors of lung^ref, breast (Nathan B, Anbazhagan R, Dyer M: Expression of bcl-2 like immunoreactivity in breast cancer. Breast 2:134, 1993),  prostate^ref or liver origin^ref, also express the bcl-2 protein. Finally, the bcl-2 protein is also detected in a number of normal tissues, including B lymphocytes of the mantle zone and normal T cell^{ref1, ref2}. Bcl-2 can be regarded as a member of a new category of oncogenes that is involved in cell survival, by blocking programmed cell death, also called apoptosis^ref. Deregulated bcl-2 extends the survival of some interleukin-dependent hematopoietic cell lines when deprived of growth factors^ref. In vivo, bcl-2-Ig transgenic mice express constitutively a high level of bcl-2 protein, and thus accumulate an excess of resting IgIWIgD B cells because of extended survival^ref. Thus, constitutive bcl-2 expression might cooperate with the activation of other oncogenes, such as c-myc, in a multistep development of lymphomas^ref. It has been shown that apoptosis occurs in a majority of lymphoid cells when treated by various antineoplastic agents commonly used in the treatment of NHLs^{ref1, ref2}. Recent in vitro studies on murine and human leukemia cell lines have demonstrated that, although not preventing suppression of cell proliferation, high levels of bcl-2 protein could protect the cells from undergoing apoptosis in the presence of glucocorticoids and multiple chemotherapic drugs^{ref1, ref2}. Taken together, these findings suggest that a high level of bcl-2 protein may play an important role both in lymphoma-genesis and in the development of drug resistance, in follicular, as well as in other varieties of lymphomas. This would provide support for the potential clinical value of bcl-2 protein expression in NHLs, as recently suggested in acute myeloid leukemias^ref and lung carcinoma^ref. However, only few studies have focused on the correlation between bcl-2 expression at the protein level and clinical presentation and outcome in follicular^ref or diffuse^{ref1, ref2} lymphomas. This prompted us to analyze the distribution of bcl-2 at the protein level according to histology and phenotype in 290 uniformly treated patients with intermediate or high-grade NHLs enrolled in the LNH87 protocol^ref. To assess its clinical significance and its potential prognostic value, we focused on the correlation between bcl-2 expression, clinical features, and outcome in diffuse large B-cell lymphomas, which is the most frequent and homogeneous immunohistological subgroup of the present series. bcl-2 is expressed by lymphoma cells with a high frequency regardless of histologic subgroups, and that high bcl-2 expression is correlated with B-cell phenotype. Furthermore,clinical correlations performed in the more homogeneous immunohistological group of diffuse large B-cell NHL disclose that high bcl-2 expression is correlated with extended stage of the disease and appears to be associated with a poor prognosis. Indeed, DFS and survival were significantly reduced in patients with high bcl-2 expression, although the independent effect of high bcl-2 expression, at the time of analysis, could be demonstrated only on DFS. To date, most studies of the bcl-2 gene have focused on the presence of the t(14; IS), which have been found in the majority of follicular lymphomas, and in about 20% of diffuse large cell lymphoma^{ref1, ref2, ref3, ref4}. It has been postulated, although not uncontroversially demonstrated, that the presence of a bcl-2 gene rearrangement or of the translocation t( 14; 18) seemed to be associated with shorter DFS andor failure to achieve a complete remission^{ref1, ref2, ref3, ref4}. In contrast, only a few studies have focused on the clinical relevance of bcl-2 expression at the protein level^{ref1, ref2}. In the present study, we further extend to a large group of patients previous reports showing that the bcl-2/124 monoclonal antibody provides accurate staining even on routine paraffin-embedded biopsy material^{ref1, ref2}. Using this antibody, we confirmed that high expression of bcl-2 is found in a large number (45%) of lymphomas with intermediate-or high-grade histology. The apparent discrepancy between the frequency of high expression of the protein and the bcl-2 gene rearrangement is consistent with the findings that bcl-2 protein is expressed in other hematologic malignancies such as acute^ref and chronic myelogeneous leukemia^ref, in a large variety of carcinomas from liver^ref, lung^ref, prostatic gland^ref as well as in normal tissues, independently of the t(14; 18) translocation^ref. These data strongly suggest that, beside the t(14; 18) translocation, other pathological mechanisms may increase the expression of bcl-2. As an example, upregulation of bcl-2 expression has already been reported in vitro as a consequence of Epstein-Barr virus (EBV) infection^ref or IL-10 stimulation (Levy E, Brouet JC: Interleukin-10 presents spontaneous death of germinal center B cells by induction of the bcl-2 protein. J Clin Invest 93:424, 1994). Alternatively, the transformation process may have occurred in subsets of normal B or T lymphocytes in which constitutive high levels of endogenous bcl-2 protein are present^ref. This study further confirms previous observations that most high-grade mucosa-associated lymphoid tissue (MALT) lymphomas are bcl-2 negative^ref, as the latter pattern was shown in 12 of the 14 large B-cell lymphomas of the gastrointestinal tract (data not shown). The absence of detectable bcl-2 protein in a number of intermediate- and highgrade lymphoma, especially in high-grade MALT lymphomas, might reflect a breakdown in bcl-2 gene expression at the transcriptional or the posttranscriptional level^ref. However, whatever the mechanism of deregulation of the bcl-2 gene, the finding of high expression of bcl-2 observed in a large proportion of NHLs raises the question of its clinical value and biological significance, because bcl-2 is now regarded as a member of a new category of oncogenes involved in blocking programmed cell death, thus leading to abnormal accumulation of cells^{ref1, ref2, ref3}. Our analysis, which was performed on fixed paraffin-embedded material, thus preserving morphology, easily identified 3 patterns of bcl-2 protein expression. We chose to individualize the group with virtually all tumor cells bcl-2 positive from the other 2 groups exhibiting either no or intermediate bcl-2 expression, because the labeling in the high bcl-2 expression group was homogeneous and easily distinguishable from the other 2. In addition, several recent in vitro and in vivo studies have pointed out the physiological and clinical importance of high bcl-2 expression^{ref1, ref2, ref3, ref4}. Furthermore, when comparing, in the present study, survival according to the level of bcl-2 expression, no difference was observed for the bcl-2^- and bcl-2 intermediate groups. In the present series, including patients who were all treated with the same induction regimen of the LNH87 protocol containing high doses of anthracyclins and cyclophosphamide^ref, we show that the patients' outcome after chemotherapy was predicted by bcl-2 expression.sion. Indeed, for the whole group, as well as for the more homogeneous subgroup of diffuse large Bcell lymphomas, relapses occurred more frequently and earlier in lymphomas of the high bcl-2 expression category. In addition, in the large B-cell NHL subgroup, survival was significantly reduced in patients with high bcl-2 expression. The prognostic differences between patients whose neoplasms show high bcl-2 expression and those that do not, may reflect different genetic and immunologic pathways for achieving similar histological tumors and clinical presentation rather than a direct effect of bcl-2. However, our finding is consistent with the recent in vitro studies of Myashita and Reed^{ref1, ref2, ref3} who reported that bcl-2 transfected murine and human lymphoid cell lines exhibit higher resistance to several antineoplastic agents, including those used in the present study. Indeed, in bcl-2 transfected cells, chemotherapy induces arrest of proliferation, but unlike in control cells, death by apoptosis is prevented, and drug withdrawal results in reinitiation of cell growth. In the more homogeneous subset of diffuse large B-cell lymphomas, high bcl-2 expression appears, in multivariate analysis, as an independent prognostic factor for DFS together with performance status. Therefore, it is not likely that the association of high bcl-2 expression with a poor clinical outcome is due to its correlation with stage III-IV disease. Moreover, the fact that high bcl-2 expression is not correlated with the level of LDH, suggests that the poor outcome is mainly due to delayed cell death or resistance to treatment, but not to increased cell proliferation. This hypothesis is consistent with the putative role of bcl-2 in lymphomagenesis, as a suppressor of apoptosis without effect on cell proliferation^ref. In contrast, the finding that high bcl-2 protein expression does not appear to affect independently overall survival of patients with diffuse large B-cell lymphomas may be due to an insufficient follow up, and thus should be reevaluated later. In conclusion, in this series of uniformly treated patients with a diffuse large B-cell lymphoma, high bcl-2 protein expression was closely linked to reduced DFS and, at a lesser extent, to shorter survival. Together with the results of recent studies^{ref1, ref2} (Kramer MHH, Hermans J, Krol S, van Groningen K, van Krieken JHJM, de Jong D, Kluin P:Bcl-2 expression in diffuse large cell lymphoma. Blood 84:444a, 1994 (abstr)) performed on a smaller number of patients and/or receiving heterogeneous treatments, it appears that bcl-2 protein expression, as evaluated in routinely paraffin-embedded tissue, may be considered as a new independent biological prognostic parameter. The bcl-2 protein expression, like the Ki67 proliferating index^ref, the presence of the lymphocyte homing receptor (CD44)^ref, or deregulation of the p53 oncogene^ref may aid in the identification of patient risk groups.^ref
• B-cell CLL/lymphoma 6 (BCL6) gene on chromosome 3q27 contains 10 exons and encodes the Bcl-6 protein consisting of 706 amino acids^{ref1, ref2, ref3}. This protein is a transcriptional repressor expressed by GC B cells, and it is necessary for GC formation^{ref1, ref2, ref3}. BCL6 functions by directly binding to specific DNA sequences and suppressing the transcription of target genes. An alternative mechanism by which BCL6 controls the transcription of genes lacking a BCL6 binding site is required for the prevention of tumor suppressor p53-independent cell cycle arrest in germinal center B cells. BCL6 interacted with the transcriptional activator Miz-1 and, via Miz-1, bound to the promoter and suppressed transcription of the cell cycle arrest gene CDKN1A. Through this mechanism, BCL6 may facilitate the proliferative expansion of germinal centers during the normal immune response and, when deregulated, the pathological expansion of B cell lymphomas^ref. Cytogenetic and molecular analyses have demonstrated that alteration of 3q27, BCL6, or both is one of the most common genetic abnormalities in B-cell tumors^{ref1, ref2, ref3}. The BCL6 gene was first identified at the breakpoints on 3q27 involved in t(3;14)(q27; q32) and t(3;22)(q27;q11) translocations in diffuse large B-cell lymphoma^{ref1, ref2, ref3, ref4}. Initial studies suggested that 3q27 translocation or rearrangement of the BCL6 gene were specifically associated with 30-40% of DLBCL^ref, but it is observed in 6.4% up to 14.3% of FL^{ref1, ref2, ref3, ref4}. Although almost all the proto-oncogenes in B-cell NHL such as c-MYC, BCL1, BCL2, BCL3, PAX5 translocate only to the IG loci^ref, the 3q27 translocation is unique in that it fuses the BCL6 gene on 3q27 not only to IG genes but also to multiple non-IG partners on other chromosomes^{ref1, ref2, ref3, ref4}. To date, > 20 partner chromosomal loci have been reported^ref. As the result of the translocation in those cases, the structure of the Bcl-6 protein is not affected^ref, but the promoter region of the BCL6 gene is substituted for that of each partner^ref, respectively, and the rearranged BCL6 gene is presumed to come under the control of the replaced promoter^ref. In addition to chromosomal translocation, the BCL6 gene in B-cell neoplasms is also affected by point mutations^{ref1, ref2}. Furthermore, there is a possibility that the same mechanism is responsible for those 2 processes^{ref1, ref2}, because the target zones within the BCL6 gene for rearrangement and for somatic mutation are overlapping. Somatic mutation of the BCL6 gene was reported to be associated with the morphologic transformation of FL^ref. Some of these mutations were reported to be associated with increased BCL6 mRNA expression; however, increased BCL6 mRNA expression is not uniformly necessary for the transformation^ref. Multiple BCL6 translocation partners in individual cases of primary gastric lymphoma (GL), including MALT lymphoma, diffuse large cell lymphoma with residual MALT lymphoma, and DLBCL^ref. Translocations juxtaposing the BCL6 oncogene next to the IGH locus occur in 20% of nodular lymphocyte predominant Hodgkin’s lymphoma (NLPHL)^ref. The higher sensitivity of 2 PCR-based techniques—long-distance inverse polymerase chain reaction (LDI-PCR) on chromosomal DNA and 5' RACE on mRNA—can detect not only the main lymphoma clone but also the emerging minor subclones with new BCL6 translocations and possibly altered pathogenicity
• CDC91L1 encodes PIG-U, a subunit of a glycosylphosphatidylinositol (GPI) transamidase-complex, which is overexpressed 5-fold in the uroepithelial cells from 30% of patients with bladder cancer (e.g. from t(5;20)(p15;q11), leding to overproduction of several GPI-anchored proteins, including uPAR (which is associated with JAK-STAT signalling), in different cell types, that confer a faster growth rate and increased anchorage-independent growth capability^ref
• murine double minute 2 (MDM2) regulates p53 via an autoregulatory feedback loop in which both proteins mutually control their cellular level. MDM2 protein has multiple options for abrogating p53 function, including blocking access of p53 to basal transcription molecules, preventing its C-terminal acetylation, and inducing p53 ubiquitination

Web resources : MDM2 Database : data on the frequency of MDM2 amplifications in human cancers
• COX-2
• stathmin 1 (STMN1) / oncoprotein 18 prevents assembly and promotes disassembly of microtubules and is phosphorylated by kinase interacting with leukemia-associated gene (stathmin) (KIS)
• kinases
• protein kinases
• serine/threonine kinases
• cyclin-dependent kinase (CDK) family
• CDK4
• CDK6
• p39 c-MOS / v-mos Moloney murine sarcoma viral oncogene homolog [Moloney murine sarcoma virus]
• c-RAF family
• B-RAF initiates downstream signalling by phosphorylating MEK, which, in turn, activates ERK. Most cancer-associated BRAF mutations affect residues in the kinase domain, indicating that increased catalytic activity is responsible for oncogenesis, but even BRAF mutants with decreased kinase activity can have oncogenic effects, through interactions with CRAF, another member of the RAF family. Altered residues in kinase domains might lead to a conformation change which could be transmitted to the CRAF kinase domain, leading to its activation^ref
• AKT / PKB
• PIM-1
• nonreceptor protein tyrosine kinase (PTKs)
• p60 c-SRC [Rous sarcoma virus]
• p145 c-ABL1 [Abelson murine leukemia virus] 9q => BCR in 22p (Ph*) in CML
• p56 LCK
• p62 c-YES
• feline sarcoma oncogene (FES) / V-FES feline sarcoma viral/V-FPS fujinami avian sarcoma viral oncogene homolog [Snyder-Theilen feline sarcoma virus] [Fujinami sarcoma virus]
• c-FGR [Gardner-Rasheed feline sarcoma virus]
• PI3KCA, which encodes the p110a catalytic subunit of PI3K, is mutated in many colon, brain (anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas^ref), gastric cancers, breast^ref and lung cancers^ref
• STK15 : T91A transition causes a Phe residue at position 31 to be replaced with Ile : the Ile³¹ variant cannot bind UBE2N, so the ubiquitin ligase remains in the cytoplasm and cannot localize to the centrosomes to regulate chromosome segregation
• specific transcription factors
• transcriptional activators for other protooncogenes
• AP-1
• p39 c-JUN [Avian sarcoma virus 17]
• c-FOS [FBJ Murine osteosarcoma virus]
• c-MYC [avian myelocytic leukemia virus] is one of the most famous oncoproteins. It contributes to
• invasion
• angiogenesis
• genomic instability by interfering with the repair of DNA DSBs => gene amplification and fusions
• sensitization to apoptotic stimuli.
• up-regulation of genes that are involved in cellular immortalization or escape from cellular senescence, as WRN.
• MYCN
Traslocation from 8q to Ig genes on chromosomes 2, 14q, and 22 causes Burkitt's lymphoma
• RARa in APL
• c-ERBA / T3R [Avian erythroblastosis virus]
• c-MAF / v-maf musculoaponeurotic fibrosarcoma oncogene homolog (avian)
• MAFA
• MAFB
• MAFF
• MAFG
• MAFK
• c-MYB / v-myb myeloblastosis viral oncogene homolog (avian) [Avian myeloblastosis virus]
• MAX
• REL
• B-LYM
• SKI / v-ski sarcoma viral oncogene homolog (avian)
• regulated in glioma (RIG)
• T-cell acute lymphocytic leukemia 1 (TAL1)
• ETS1 / v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) [Avian erythroblastosis virus]
• ETS2 / v-ets erythroblastosis virus E26 oncogene homolog 2 (avian) [Avian erythroblastosis virus]
• ELK-1, member of ETS oncogene family
• ERG-1 / CUB and zona pellucida-like domains 1 (CUZD1)
• ERG-2
• glioma-associated oncogene homolog (GLI)
• Oct-3/4 contributes exclusively  to germ-cell neoplasia from an early stage and is required for tumour maintenance^ref
• transcriptional repressors of tumour suppressor genes
• Pokemon (encoded by the Zbtb7 gene) is a critical factor in oncogenesis. Mouse embryonic fibroblasts lacking Zbtb7 are completely refractory to oncogene-mediated cellular transformation. Conversely, Pokemon overexpression leads to overt oncogenic transformation both in vitro and in vivo in transgenic mice. Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding. Pokemon is aberrantly overexpressed in human cancers and its expression levels predict biological behaviour and clinical outcome. Pokemon's critical role in cellular transformation makes it an attractive target for therapeutic intervention^ref
• E1A
• EMSY (amplified in 13% of breast cancers and 17% of ovarian cancers)
• matriptase / membrane-type serine protease / suppression of tumorigenicity 14 : the first known cell-surface protease that can act as an oncogene^{ref1, ref2}
• nucleophosmin / NPM / B23 / NO38 is a nucleolar protein that specifically associates with the bodies of mRNAs as a result of the process of 3'-end formation. NPM deposition requires polyadenylation but not the 3' cleavage event to occur on the transcript. Furthermore, the protein does not associate with RNAs bearing a preformed poly(A) tail or with mRNAs that have undergone cleavage but not polyadenylation. A region within 10 bases upstream of the AAUAAA element is required for NPM association, but deposition of the protein seems to be sequence independent. NPM association with poly(A)⁺ mRNAs was also demonstrated in vivo. NPM, therefore, represents a mark left on transcripts as a result of 3'-end processing and may have a role in one or more of a variety of post-transcriptional processes influenced by the polyadenylation event^ref. It is directly implicated in cancer pathogenesis, as the NPM1 gene is found mutated and rearranged in a number of haematological disorders : 27.5% of acute myeloid leukemia (AML). Furthermore, the region of chromosome 5 to which NPM1 maps is deleted in a proportion of de novo human myelodysplastic syndromes (MDS), and loss of chromosome 5 is extremely frequent in therapy-related MDS. NPM is a multifunctional protein, and its role in oncogenesis is controversial as NPM has been attributed with both oncogenic and tumour suppressive functions. A hypomorphic Npm1 mutant series (Npm1^+/- < Npm1^hy/hy < Npm1^-/-) was generated in mouse. Npm is essential for embryonic development and the maintenance of genomic stability. Npm1^-/- and Npm1^hy/hy mutants have aberrant organogenesis and die between embryonic day E11.5 and E16.5 owing to severe anaemia resulting from defects in primitive haematopoiesis. Npm1 inactivation leads to unrestricted centrosome duplication and genomic instability. Npm is haploinsufficient in the control of genetic stability and that Npm1 heterozygosity accelerates oncogenesis both in vitro and in vivo. Notably, Npm1^+/- mice develop a haematological syndrome with features of human MDS. Our findings uncover an essential developmental role for Npm and implicate its functional loss in tumorigenesis and MDS pathogenesis^ref
Activation mecahanisms for proto-oncogenes :
• overexpression due to gene amplification of a normal gene
• double minute (DM)
• homogeneously staining regions (HSR) : long unbanded regions on chromosomes created by gene amplification; they are tumor markers indicative of solid neoplasms with poor prognosis.
• extended chromosome regions (ESR)
• macrobands
E.g.
• c-MYC in adenocarcinomas, squamous cell carcinomas, sarcomas, medulloblastomas
• N-MYC
• ErbA
• ErbB1
• ErbB2
• MET
• normal expresion of a mutated gene
• point mutations : e.g.
• HRAS
• KRAS
• NRAS in CML and ALL
• insertions : e.g.
• c-MYC in mammary ductal adenocarcinoma
• reciprocal unbalanced chromosomal translocations :
• with overexpression of one of the normal genes due to position effect : e.g.
• BCL2
• c-MYC in Burkitt lymphoma and ATL
• MOS
• TAL1
• with formation of a fusion protein whose expression level depends on that of source genes : e.g.
• BCR/c-Abl in CML (Ph* chromosome)
• RET
• tumour suppressors : usually they are direct inhibitors of proto-oncogenes; mutation of both alleles is required for carcinogenesis
• caretaker genes : their mutations are more malignant than those of gatekeeper genes as they cause clastogenias
• mutS homolog 2 (MSH2), colon cancer, nonpolyposis type 1 (HNPCC) in Muir-Torre syndrome
• mutS homolog 3 (E. coli) (MSH3)
• mutS homolog 6 (E. coli) (MSH6) / GTBP
• mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1)
• mutL homolog 3 (E. coli) (MLH3)
• in humans, breast cancer 1 (BRCA1) and BRCA2 encode large, nuclear-localized proteins of 1,863 and 3,418 amino acids, respectively. The sequence of the proteins provides few clues as to their biological roles, because they are devoid of significant similarity to molecules of known function. Importantly, BRCA1 and BRCA2 do not resemble one another, despite the sometimes confusing similarities in nomenclature. For example, the 2 BRCT domains that are found at the carboxyl terminus of BRCA1 are 100-residue structures that mediate protein-protein interactions. They bear no resemblance to the similarly named BRC repeats in BRCA2, which are evolutionarily conserved peptide motifs of 30-40 amino acids each, that recur 8 times in all known vertebrate BRCA2 molecules and are implicated in binding RAD51 / RecA homolog
• BRCA1 : humans and dogs share about 96% of the same coding sequence within the gene, while humans and rodents share only about 65% of the genetic coding. BRCA1 is mutated in 8% of all breast cancer : among the known BRCA-1 mutations, sites within the genetic coding that are likely targets of mutation are the same sites conserved among humans, dogs, rats and mice, and among the conserved amino acids that make up the BRCA-1 protein in the 4 species, the amino acids that are most likely to be mutated are those that are hydrophobic. BRCA1 is a transcriptional repressor of ERa and participates in DNA repair. BRCA1 localizes to both the unpaired X chromosome in the XY body of male pachytene spermatocytes and the inactive X (Xi) chromosome in female somatic cells : susceptibility to breast cancer occurs only in females who inherit a mutation in BRCA1 as mutated BRCA1 inhibits the non-coding XIST RNA localization to the Xi chromosome, reactivating genes that are normally silent on the Xi. Women with BRCA-1 mutation are twice as likely to give birth to girls, thus passing on the vulnerability). BRCA1-IRIS as a 1,399-amino-acid BRCA1 gene product encoded by an uninterrupted open reading frame that extends from codon 1 of the known BRCA1 open reading frame to a termination point 34 triplets into intron 11. Unlike full-length BRCA1 (p220), BRCA1-IRIS is exclusively chromatin-associated, fails to interact with BARD1 in vivo or in vitro and exhibits unique nuclear immunostaining. Unlike BRCA1FL (or p220), BRCA1-IRIS also co-immunoprecipitated with DNA-replication-licensing proteins and with known replication initiation sites. Suppression of BRCA1-IRIS expression hindered the normal departure of geminin from pre-replication complexes, and depressed the rate of cellular DNA replication and possibly initiation-related synthesis. In contrast, BRCA1-IRIS overexpression stimulated DNA replication. These data imply that endogenous BRCA1-IRIS positively influences the DNA replication initiation machinery^ref.
• BRCA2 (deleted in 2% of breast cancer) : wild-type BRCA2 ...
• binds to RAD51 / RecA homolog through 6 of its 8 so-called BRC repeats (BRC1-8), controlling RAD51 oligomerization. Although it is not part of the normal replication machinery, BRCA2 localizes in the nuclear foci that are formed when replication is inhibited. BRCA2 is required to  prevent the breakdown of stalled replication forks and disruption of this function leads to the chromosomal rearrangements that occur spontaneously in dividing BRCA2-mutant cells^ref.
• enhances the transcriptional activity of AR by 10-fold by synergizing with GRIP1
The mutant form of BRCA2 ...
• cannot bind RAD51, preventing repair of damaged DNA
• cannot enhance AR activity
Families with only the BRCA-2 gene have roughly equal proportions to give birth to boys and girls. Biallelic germline mutations in BRCA2 are associated with the very rare complementation group of Fanconi anaemia. The clinical features of FA-D1 patients - who develop Wilms' tumour, breast cancer and medulloblastoma, differ from typical FA cases. BRCA and FA proteins work in a network of connected biological processes, and not in a linear sequence of evens that constitutes a single "pathway".
BRCA2 carriers are at increased risk for cancers of the prostate (RR = 2.5) and pancreas (RR = 5.9), and possibly bone (RR = 14.4) and pharynx (RR = 7.3)^ref
• BRCA3
• ataxia telangiectasia mutated (ATM : includes complementation groups A, C and D) in ataxia teleangiectasia (AT). The related kinases ATM and ataxia-telangiectasia and Rad3-related (ATR) phosphorylate a limited number of downstream protein targets in response to DNA damage. ATM kinase signals the DNA damage response by targeting the transcriptional cofactor serine/threonine kinase receptor associated protein (STRAP). ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex. Strap activity enhances p53acetylation, and augments the response to DNA damage. Strap remains localized in the cytoplasm in cells derived from ataxia telangiectasia individuals with defective ATM, as well as in cells expressing a Strap mutant that cannot be phosphorylated by ATM. Targeting Strap to the nucleus reinstates protein stabilization and activates the DNA damage response. These results indicate that the nuclear accumulation of Strap is a critical regulator in the damage response, and argue that this function can be assigned to ATM through the DNA damage-dependent phosphorylation of Strap^ref.
• PMS1 postmeiotic segregation increased 1 (S. cerevisiae)
• PMS2 postmeiotic segregation increased 2 (S. cerevisiae)
• fragile histidine triad (FHIT) gene
• Bloom syndrome (BLM)
• Werner syndrome (WRN)
• Fanconi anemia, complementation group A (FACA / FANCA)
• Fanconi anemia, complementation group C (FACC / FANCC)
• MRE11
• MRE11 meiotic recombination 11 homolog A (MRE11A) (S. cerevisiae)
• MRE11 meiotic recombination 11 homolog B (MRE11B) (S. cerevisiae)
• p95 Nijmegen breakage syndrome 1 (nibrin)
• xeroderma pigmentosum, complementation group A (XPA)
• xeroderma pigmentosum, complementation group C (XPC)
• gatekeeper genes
• negative growth factors
• TGF-b loss of signalling in stromal fibroblasts leads to oncogenic changes in adjacent epithelial cells by upregulating HGF / SF and c-Met / HGF-R expression, whose signalling upregulates c-Myc and downregulates Waf1 and Kip1 expression^ref

Web resources : The TGF-b system : TGF-b family, their receptors, and SMAD transcription factors, by Joan Massagué
• TNF-a
• IFN-g
• IL-24
• receptors for negative growth factors
• intracellular transductors
• pNF1 / neurofibromin (Ras-GAP) in type 1 neurofibromatosis or von Recklinghausen's disease
• DPC4 / SMAD4
• FBXW7/hCDC4 is a haploinsufficient p53-dependent tumour suppressor gene that encodes a ubiquitin ligase implicated in the control of chromosome stability. Its loss leads to genetic instability by mechanisms that might involve the activation of Aurora-A, providing a rationale for the early occurrence of these mutations in human cancers.

^ref
• cyclin-dependent kinase inhibitors (CKIs / CDIs)
• CDKN1A / p21^Cip1/Waf1
• CDKN2Aencodes the tumour suppressors :
• INK4A
• ARF
• CDKN1B / p27^Kip1
• proapoptotic BCL2 family members
• adenomatous polyposis coli (APC) : mutations cause  familial adenomatous poliposis (FAP)


APC encodes a 2843-amino-acid protein with 6 major domains: an oligomerization region (O), armadillo repeats (ARM), 15-amino-acid repeats (15 AA), 20-amino-acid repeats (20 AA), a basic region, and a domain involved in binding EB1 and the Drosophila discs large homologue (E/D). Shown are the positions within the APC gene of a total of 650 somatic and 826 germline mutations. The vast majority of these mutations result in the truncation of the APC protein. Germline mutations are found to be relatively evenly distributed up to codon 1600 except for 2 mutation hotspots at amino acids 1061 and 1309, which together account for one-third of the mutations found in familial adenomatous polyposis (FAP) families. Somatic APC mutations in colon tumors cluster in an area of the gene known as the mutation cluster region (MCR). The location of the MCR suggests that the 20-amino-acid domain plays a crucial role in tumor suppression. Note that loss of the second functional APC allele in tumors from FAP families often occurs through loss of heterozygosity.
Web resources : Thierry Soussi's lab on p53 and APC at Institute Curie
• deleted in colorectal carcinoma (DCC)
• ARC1 / uvomorulin / E-cadherin. The phenotypic changes of increased motility and invasiveness of cancer cells are reminiscent of the epithelial–mesenchymal transition (EMT) that occurs during embryonic development. Snail, a highly unstable zinc-finger transcription factor with a short half-life about 25 min, triggers this process by repressing E-cadherin expression. GSK-3b binds to and phosphorylates Snail at 2 consensus motifs to dually regulate the function of this protein. Phosphorylation of the first motif regulates its b-Trcp-mediated ubiquitination, whereas phosphorylation of the second motif controls its subcellular localization. A variant of Snail (Snail-6SA), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce EMT. Furthermore, inhibition of GSK-3b results in the upregulation of Snail and downregulation of E-cadherin in vivo. Thus, Snail and GSK-3b together function as a molecular switch for many signalling pathways that lead to EMT^ref.
• pNF2 / neurofibromin 2 in type 2 neurofibromatosis
• DUBs : TRE2 / USP6
• CDC4 / FBXW7 is an E3 ubiquitin ligase that targets cyclin E (which regulates G1-S transition and chromosome stability) for degradation^ref
• kinases
• protein kinases in STPs from negative growth factor
• phosphatases
• protein phosphatases
• PP2R1B (b isozyme of A subunit of PP2A)
• PTP
• PTEN phosphatase has long been known to have tumour-suppressive activity through its ability to antagonize te PI3K-AKT signalling pathway. The C2 domain of PTEN inhibits cell motility independently of the PI3K-AKT pathway : the C2 domain is inactive when it is phosphorylated and activation by dephosphroylation of Thr³⁸³ enables PTEN to interfere with migration^ref
• specific negative transcription factors
• tumour protein of 53 kDa (TP53) is a sequence-specific DNA-binding nuclear protein that acts to induce gene expression. Overall, the program of p53-activated genes is associated with suppression of cell growth, consistent with our understanding of the action of anti-oncogenes. Mutations of p53 may not only inactivate its growth-suppression function, but can actually generate a genetically dominant, functional oncogene. Human tumors associated with p53 mutations include those of hematopoietic tissues (e.g., 20% of multiple myelomas), bladder, liver, brain, breast, lung, and colon. It is likely the most frequently mutated gene in human cancer. P53 has both pro-apoptotic functions and prevents genome instability - possibly by inducing cell-cycle arrest : the latter is preserved even in Trp53^515C/515C mutant, which corresponds to an arginine to proline amino-acid substituion at residue 172^ref. Loss of p53 characteristically results in highly aneuploid cells as control over centrosome duplication is removed, but this is not the case in the Trp53^515C/515C cells. Inherited loss of functions results in Li-Fraumeni syndrome. p53-regulated angiogenic molecules :
• genes upregulated by p53
• thrombospondin-1 (TSP1) is an endogenous angiogenesis inhibitor^{ref1, ref2}
• brain-specific angiogenesis inhibitor 1 (BAI1)^ref
• MMP2 promotes endogenous antiangiogenic peptide formation from basement membrane proteins^ref
• Eph receptor A2 (EphA2) induces apoptosis; soluble EphA2 receptors are anti-angiogenic^{ref1, ref2, ref3}
• genes downregulated by p53
• MMP1 promotes angiogenesis in bone and activates latent MMP2^{ref1, ref2}
• COX-2 promotes angiogenesis^ref
• VEGF-A is a potent pro-angiogenic and permeability factor^ref
• HIF-1a induces angiogenesis by activation of VEGFA transcription under hypoxic conditions^ref
Web resources :
• Thierry Soussi's lab on p53 and APC at Institute Curie
• TP53 mutation database by the International Agency for Research on Cancer (IARC)
• p110 retinoblastoma 1 (RB1) : the prototypical tumor suppressor gene Rb behaves in a genetically recessive fashion. Elimination or inactivation of both Rb gene copies is required for manifestation of the tumorigenic phenotype, first recognized in children with retinoblastoma. Such children inherit only a single functional copy; subsequent mutagenic inactivation of the remaining allele results in tumor susceptibility. Rb acts to sequester a group of transcription factors, termed E2F, which regulate genes critical for DNA synthesis. Alterations of Rb alleles are found in approximately 30% of human acute leukemias. RB1 binds to RBP (not for other pocket proteins) : mutations promote tumour development by deregulating the E2F family of transcription factors leading to uncontrolled cell cycle progression. The mitotic checkpoint protein Mad2 is a direct E2F target and, as a consequence, is aberrantly expressed in cells with Rb pathway defects. Concordantly, Mad2 is overexpressed in several tumour types, where it correlates with high E2F activity and poor patient prognosis. Generation of Rb pathway lesions in normal and transformed cells produces aberrant Mad2 expression and mitotic defects leading to aneuploidy, such that elevated Mad2 contributes directly to these defects^ref.

Web resources : RB1 gene mutation database by Dietmar Lohmann at the Institut für Humangenetik in Essen, Germany
• RBL2 / Rb2/p130 :
• p52 Wilms tumor 1 (WT1) inhibits EGR, TFs in WAGR syndrome
• myogenic regulatory factor (MYOD1)
• VHL (TF for elongin C) in von Hippel-Lindau syndrome (VLS)
• E2F1
• SNF5 / INI1
• b-catenin
• ovarian cancer 1 (OVCA1), despite its role as a positive regulator of cell-cycle progression, is a tumour suppressor, and causes proliferation defects only when its loss is combined with that of p53^ref
• ADP-ribosylation factor 1 (ARF1) is activated in response to a range of oncogenic signals : Arf is difficult to detect in vivo probably because cells that express Arf die or undergo growth arrest^ref
• beclin 1 (BECN1) autophagy gene is monoallelically deleted in up to 75% of ovarian cancers, 50% of breast cancer and 40% of prostate cancers. However, biallelic inactivations have not been found, so it is not a classical tumour-suppressor gene^ref. Genes best known for inducing cell growth or inhibiting apoptosis - such as PI3K, AKT and PTEN - are also involved in autophagy.
• BubR1, a component of the mitotic chekpoint machinery, is significantly reduced in cancer cells causing polyploidy^ref
• peroxiredoxin is an antioxidant which protects from oxidative DNA damage
• TIMPs and serpins
• Kruppel-like factor 6 (KLF6) inactivated in > 50-60% of all prostate cancers^ref, colorectal cancers^ref, glioblastoma multiforme^ref, and hepatocellular carcinoma (HCC)^ref.
• deletion, mutation or methylation of ADP-ribosylation factor-like tumor suppressor 1 (ARLTS1) occurs in familial forms of chronic myeloid leukemia, or thyroid, colorectal, breast, lung or early stage pancreatic cancer
• oncosuppressor RNAs :
• H19, imprinted maternally expressed untranslated mRNA
• sub-cellular mislocalization
• forkhead (FOXO) family member 1a (FOXO1A) is exported from the nucleus to the cytoplasm in PTEN-null cells^ref
• microRNAs can trigger tumours by regulating proteins that disrupt normal cellular growth. Everybody has been focused on understanding how proteins fit into cancer-causing pathways, but there is another regulatory pathway that controls not the protein product but its utilization. Some microRNAs can accelerate the development of cancer when transplanted into mice^ref. The discovery should also help researchers to identify the type of cancer that an individual has, a step that is crucial in assigning treatment. Different types of tumour express different levels of microRNAs^ref. By measuring the levels of expression of 217 genes in different types of cancers, microRNA 'profiles' of many cancers could be used to diagnose the origin of tumours that are difficult to classify by the traditional method of looking at cell shape and character under a microscope. MicroRNA profiling also worked better than existing genetic profiling methods, correctly diagnosing 12 of 17 tricky tumours. The existing method diagnosed only one of these tumours correctly. Others note that the discovery could have knock-on effects for treatment strategies. MicroRNAs are potentially therapeutic : you could deliver them to tumours, maybe in combination, or even along with chemotherapeutic drugs
DNA palindromes appear frequently and are widespread in human cancers, and identifying them could help advance the understanding of genomic instability. While the scientists did not find similar widespread palindrome formation in 4 normal cell lines studied, I anticipate we will identify palindromes on the somatic chromosomes of normal cells that might not have been mapped yet. In 2002, the molecular mechanisms for palindrome formation in the protozoan Tetrahymena was found to be conserved in mammalian cells : it is an initial, rate-limiting step in gene amplification^ref. Given amplification of large genomic regions contributes to tumor progression, the investigators explored what role DNA palindromes—already known to exist on the normal human Y chromosome—might play in human cancers. Palindromes are difficult to study due to their propensity for rapid intrastrand base pairing. In a new technique, if DNA containing palindromic regions is denatured and rapidly renatured, the results are double-stranded snap-back DNA near palindromic centers and largely single-stranded DNA in nonpalindromic regions. The snap-back DNA is resistant to single-strand–specific nuclease S1, while the rest is sensitive. When the researchers combined their technique with a cDNA-spotted array, widespread palindrome formation was not seen in one breast epithelial or 3 different fibroblast cell lines. The sensitivity is terrific, able to detect signal in a 1:40 dilution from a cell line containing only a couple of copies of the palindrome. This research provides another mechanism to investigate genomic instability and therefore will likely become widely used by both cancer and basic researchers. In the Colo320DM human colon cancer cell line, 150 genes tested significantly higher for palindromes than baseline, with significant overlap of palindrome-positive genes with breast cancer cell line MCF7. While most of the palindrome-positive genes seen in Colo320DM and MCF7 are not linked with an increase in gene copy number, as a whole these genes are more likely than any other loci to be amplified. This indicates only certain regions might be susceptible to further gene amplification. So the location of a tumor's palindromes might determine its ability to amplify genes and progress to higher stages of cancer. Others might criticize the findings because the technique might be measuring unknown features aside from palindromes. But those features, if they exist, are structures not yet imagined yet
Mutation types in human cancer :

Proportion of somatically mutated human cancer genes with translocations :

Dominant and recessive germline (a) or somatic (b) mutations in human cancer genes :

Proportion of genes with germline (a) or somatic (b) mutations associated with different tumour types :

Nuclei removed from mouse brain tumor cells and transplanted into mouse eggs whose own nuclei have been removed, give rise to cloned embryos with normal tissues, even though the mutations causing the cancer are still present : the finding demonstrates that the cancerous state can be reversed by reprogramming the genetic material underlying the cancer, and that genetic mutations alone are not always sufficient to cause a cell to become cancerous.
Oncogenes such as E1A and MYC are able to initiate both cell proliferation and cell death. E.g. E1A coordinates both processes by using the same machinery - E2F - to initiate them : caspase induction is not sufficient to induce apoptosis and, instead, seems to sensitize cells to apoptotic stimuli coming from p53-dependent pathways.
Nuclear transplantation of a cancer cell nucleus into an oocyte can reverse its cancer phenotype and produce embryonic stem cells (ESCs) with developmental potential. Although some of the cancer cell nuclei were unable to induce development, others supported organized division cleavages and produced blastocysts, while one of these, from an artificial Ras-inducible melanoma, also gave rise to embryonic stem cells, termed NT ES cells : injection of these cells into blastocysts allowed the production of chimeric mice, in which the NT ES cells contributed to multiple organs, including the skin, heart, and liver. Nevertheless, as expected, the genetic changes possessed by the original melanoma, revealed to be various chromosomal aberrations, were not reversible, resulting in the chimeric mice all developing tumors. Nonetheless, it is clear that a melanoma cell can give rise to a normal immune system, among other normal tissues, despite its multiple genetic defects
Web resources :
• Catalogue of Somatic Mutations in Cancer (COSMIC) by the Cancer Genome Project, bnased at The Wellcome Trust Sanger Institute
• Cancer Chromosomes database integrates information from the NCI Mitelman Database of Chromosome Aberrations in Cancer, the NCI Recurrent Aberrations in Cancer database, and the NCI SKY/M-FISH & CGH Database
• Oncomine 2.0 (O2) - cancer microarray database : tools to query and visualize cancer microarray data for a gene or cancer type of interest
• A 'module map' showing conditional activity of expression modules in cancer at University of Stanford^ref
• Genes and disease: cancer at NCBI
• A subway map of cancer pathways at Nature Reviews Cancer
• The tumour gene database (TGDB) : proto-oncogenes and tumour-suppressor genes
• Oncogene at COPE
• Telomeres from Kimball's biology pages
• Telomeres and telomerase-related sites by Tom Cech
• Telomere information database by Washington University.
• Prostaglandins (PGs) and cancer
• The Familial Cancer Database (FaCD) from the International Union against Cancer (UICC)
• Morphology
• Plimmer's cancer bodies : small round capsulated bodies found in cancer, and thought by the discoverer to be the parasite causing the disease but now considered to be cell necrosis products
• Gompertz growth curve is f_G(x) = a ^. e^{(-e^ (-k . (x-c))}, where ...
• x : independent variable
• a : the upper border
• k : a scale factor (also a big influence to the max. slope)
• c : (c/f_G(x)) is the inflection value
• the maximum growth rate occurs at 1/e, the point at which the tumor is about 37% of its maximum size (marked with an X).
• initial diagnosis usually occurs when y = 10⁹ cells (or 10¹⁰ cell, ie. tumor weighs 1 g) = 1 cm³
• clinical failure usually occurs when y = 10¹² cells, ie. tumor weighs 1 kg
Efforts to treat the tumor and reduce its size can result in an increase in the growth fraction and an increase in growth rate.

• Atlas of genetics and cytogenetics in oncology and haematology
• Tumor atlas at Weizmann Institute
• tumor size is measured using a Vernier caliper across its 2 perpendicular diameters and its depth, and its volume is calculated using the formula V= (4/3)pabc

Cell types in children : ovary (45%), sacrococcygeal region (40%, causing dystocia), testes, retroperitoneum, mediastinum (=>respiratory distress) , nasopharynx, intracranium, neck and stomach(monodermoma : a tumor that has developed from one germ layer)		benign tumor	malignant tumor
epithelial cells Laboratory examinations : IHC with epithelial markers (cytokeratins 1, 5, 10, 14; EGFR, b2-microglobulin)		adenoma : a benign epithelial tumor in which the cells form recognizable glandular structures or in which the cells are clearly derived from glandular epithelium adenoma alveolare : an adenoma whose cells are arranged like those of an alveolar gland.  mucinous adenoma : an epithelial tumor whose cells produce mucin.  embryonal or trabecular adenoma : a follicular adenoma whose cells are closely packed to form cords or trabeculae, with only a few small follicles  tubular adenoma : an adenoma whose cells are arranged in tubules, as occurs with adenomatous polyps of the colon, some fibroadenomas of the breast, and androblastoma.  papilloma / papillary tumor / villoma / villous papilloma or tumor : a benign epithelial neoplasm producing finger-like or verrucous projections from the epithelial surface polyp : a morbid excrescence, or protruding growth, from mucous membrane; classically applied to a growth on the mucous membrane of the nose, the term is now applied to such protrusions from any mucous membrane.	carcinoma : a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases  adenoid cystic, adenocystic or cribriform carcinoma / cylindroma : carcinoma characterized by bands or cylinders of hyalinized or mucinous stroma separating or surrounded by nests or cords of small epithelial cells. It appears as one or more of 3 patterns: cribriform carcinoma solid carcinoma tubular carcinoma Malignant and invasive but slow growing, it spreads by infiltrating the bloodstream and perineural spaces  adnexal carcinoma : carcinoma forming structures resembling the cutaneous appendages, particularly the sweat or sebaceous glands. basosquamous or metatypical cell carcinoma : carcinoma that histologically exhibits both basal and squamous elements. cancer or carcinoma in situ / preinvasive carcinoma : a neoplastic entity wherein the tumor cells are confined to the epithelium of origin, without invasion of the basement membrane; the likelihood of subsequent invasive growth is presumed to be high carcinoma medullare, molle or spongiosum / medullary carcinoma / cerebriform, encephaloid, medullary, or soft cancer or carcinoma : carcinoma composed mainly of epithelial elements with little or no stroma; sites where this is commonly found are the breast and thyroid gland scirrhous cancer or carcinoma / scirrhoma / fibrocarcinoma / carcinoma fibrosum : carcinoma with a hard structure owing to the formation of dense connective tissue in the stroma metaplastic carcinoma adenosquamous carcinoma : areas of glandular, squamous, and large-cell differentiation sarcomatoid carcinoma (SC) / pseudosarcoma : sarcomatoid transformation of a carcinoma histologically resembling a sarcoma. Current terminological preferences are such that several formerly used terms--including "spindle-cell carcinoma," "pulmonary blastoma," "squamous cell carcinoma with pseudosarcomatous stroma," "pseudosarcoma," and "carcinosarcoma"--are now encompassed by the more generic designation of "sarcomatoid carcinoma." polymorphic sarcoma type : sarcomatoid components are polymorphic spindle cell type : sarcomatoid components consisted of spindle cells osteoclastic giant cell type : a huge number of osteoclastic giant cells in the sarcomatoid components myxocartilage type : myxocartilaginoid components are seen in the tumor tissue spindle cell carcinoma / monophasic sarcomatoid carcinoma : carcinoma, usually of the squamous cell type, marked by fusiform development of rapidly proliferating cells villous carcinoma / carcinoma villosum : carcinoma in which the cells are arranged in a villous pattern, as papillary projections which are covered with neoplastic epithelium; usually seen in the gastrointestinal tract epidermoid, prickle, planocellular or squamous cell carcinoma (SCC) : carcinoma developed from squamous epithelium, having cuboid cells and characterized by keratinization and often by preservation of intercellular bridges. Initially local and superficial, the lesion may later invade and metastasize adenocarcinoma : carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures; adenocarcinomas may be classified according to the predominant pattern of cell arrangement acinar, acinous or acinic cell carcinoma, adenocarcinoma or tumor : a slow-growing malignant tumor characterized by acinic cells arranged in small glandlike structures, usually occurring in the pancreas or salivary glands, particularly in females adenoacanthoma : an adenocarcinoma in which some or the majority of the cells exhibit squamous differentiation alveolar adenocarcinoma papillary or polypoid adenocarcinoma / dendritic cancer : an adenocarcinoma in which the tumor elements are arranged as finger-like processes or as a solid spherical nodule projecting from an epithelial surface tubular carcinoma or cancer : an adenocarcinoma in which the cells are arranged in the form of tubules ... or according to a particular product of the cells, as mucinous adenocarcinoma  colloid, gelatinous, mucinous, muciparous, or mucous cancer, carcinoma or adenocarcinoma / carcinoma mucosum or muciparum : an adenocarcinoma that produces mucin in significant amounts signet-ring cell carcinoma or adenocarcinoma : signet-ring cell (one in which the nucleus has been pressed to one side by an accumulation of intracytoplasmic mucin) serous adenocarcinoma clear cell adenocarcinoma or carcinoma / mesonephroma : a rare malignant tumor of the female genital tract, resembling a renal cell carcinoma and containing tubules or small cysts with some cells that are hobnail-shaped and others whose cytoplasm is clear, containing abundant glycogen (hence "clear" during staining after fixation for microscopy) and inconspicuous stroma. It arises from multipotent serous mullerian cells and may occur in the ovary, uterus, cervix, vagina, and bladder Aetiology : one form has been linked to in utero exposure to diethylstilbestrol (DES)
mesenchymal cells => connective-tissue tumor : any tumor developed from some structure of the connective tissue	bone tissue	chondroma osteolipochondroma : a benign cartilaginous tumor containing osseous and fatty elements osteoma	sarcoma : any of a group of tumors usually arising from connective tissue, although the term now includes some of epithelial origin; most are malignant	chondrosarcoma osteosarcoma
	fatty tissue	lipoma osteolipoma : lipoma with osseous metaplasia topholipoma : a lipoma containing tophi		soft tissue sarcoma (STS) : a general unnatural term used by clinicians and for convenience by pathologists for a malignant sarcoma derived from extraskeletal connective tissue (as opposed to those of the soft epithelial tissues), with almost all lesions originating from primitive mesoderm. Not included are the reticuloendothelial system, glia and supporting tissues	liposarcoma (12-33%)
	fibrous tissue	fibroma / fibroid tumor : a tumor composed mainly of fibrous or fully developed connective tissue  cystic fibroma : a fibroma that has undergone cystic degeneration. hard fibroma / fibrum durum : one composed of fibrous tissue with few cells			fibrosarcoma (6-40%) : a malignant tumor composed of cells and fibers derived from fibroblasts, which produce collagen but otherwise lack cellular differentiation; it is grossly grayish white and firm, invades locally, and metastasizes hematogenously. Several varieties occur: an aggressive adult form, a rarely metastasizing infantile or congenital form, an inflammatory form, and a postirradiation form.  osteogenic fibrosarcoma : from anaplastic fibroblasts in any area of osseous metaplasia. Cells contain microcrystals of hydroxyapatite seen at TEM
	myocytoma : a tumor made up of myocytes.  smooth muscle tissue rough muscle tissue	leiomyoma rhabdomyoma			leiomyosarcoma (2-11%) rhabdomyosarcoma (3-20% in adults; 50% in childhood)
	peripheral nervous system (PNS)	glioma			neurofibrosarcoma (5-7%)  gliosarcoma
	vascular tissue	angioma  hemangioma lymphagioma			angiosarcoma (3%)  hemangiosarcoma hemangiopericytoma lymphangiosarcoma mesenchymal perivascular epithelioid cell tumours (so-called PEComas) : coexpression of melanocytic (HMB-45) and muscle (MyoD1) markers  angiomyolipoma lymphangioleiomyomatosis (LAM) clear cell sugar tumor of the lung clear cell myomelanocytic tumor of ligamentum teres/falciform ligament abdominopelvic sarcoma of perivascular epithelioid cells
	histiocytes				malignant fibrohistiocytoma (20%)
	synovial tissue				synovial sarcoma (4-10%)
	uncertain origin				2-5% epithelioid sarcoma : a rare, frequently metastatic tumor consisting of lobulated masses of spindle and epithelioid cells surrounding a necrotic center; it usually arises in the deep soft tissues of the distal extremities in young adults, particularly males. alveolar soft part sarcoma : a well-circumscribed, slow growing, painless, highly metastatic malignant neoplasm of unknown cell origin, characterized by a distinctive alveolar pattern and occurring predominantly in the extremities (thigh) of adult females, or head (orbit) and neck of children. On the contrary of most sarcomas, it also causes hematogenous metastases to lung, brain, bones, and arterovenous fistulae. Cytoplasm is rich of mitochondria and SER, lipid vacuoli, and rod-like crystalline structures surrounded by membranes spindle cell sarcoma : a type of soft tissue sarcoma whose cells are spindle-shaped; it is usually resistant to radiation therapy and may be of either high or low grade malignancy. telangiectatic sarcoma : a sarcoma that develops a rich vascular network; the endothelial cells may be mistaken for the neoplastic element.
embryoma / embryonal tumor : any neoplasm thought to be derived from embryonic cells or tissues, such as a dermoid cyst, teratoma, primitive neuroectodermal tumor, embryonal carcinoma or sarcoma, nephroblastoma, or hepatoblastoma germ cell tumors (GCT) : any of a group of tumors arising from primitive germ cells (PGCs), usually of the testis or ovary. Oct-3/4 is almost exclusively in GCTs and the level of expression is related to the immaturity—and hence the malignancy—of the tumor. Types include : benign GCTs : mature or benign cystic teratoma / dermoid cyst / teratoblastoma / dysembryoma / organoid or teratoid tumor (80-90% of al teratomas) : teratoma of the testis, usually found in young women, presumably derived from the ectodermal differentiation of totipotential cells, lined by apparent skin and its associated adnexal structures, and typically filled with a sebaceous caseous material in which is found hair didermoma / bidermoma : a teratoma composed of cells and tissues derived from 2 cell layers tridermoma : a teratoma containing representatives of all 3 germ layers. sequestration cyst : collection of cancerous cells which form cysts that contain one or more of the 3 primary embryonic germ layers: skin, hair or teeth.  Epidemiology : 1 every 40,000 newborns; female-to-male ratio 3:1 Localizations :  in children : ovary (45%), sacrococcygeal region (40%, causing dystocia), testes, retroperitoneum, mediastinum (=>respiratory distress) , nasopharynx, intracranium, neck and stomach in adults : in the ovary or testis Therapy : surgical resection gonadoblastoma : rare, it contains all gonadal elements, including germ cells, sex cord derivatives, and stromal derivatives and is frequently associated with an abnormal chromosomal karyotype. It may give rise to development of a dysgerminoma or other more malignant GCT. Localizations : usually arising in dysgenetic gonads (ovary or testis), often bilaterally malignant GCTs : yolk sac tumor (YST) or carcinoma / endodermal sinus tumor (EST) / adenocarcinoma of infantile testis / infantile or juvenile embryonal carcinoma : a malignant GCT of children 1-5 years old that represents a proliferation of both yolk sac endoderm and extraembryonic mesenchyme (43-9F mAb+). YST is characterized by numerous patterns including labyrinthine glandular (similar to rat placenta with Schiller-Duval bodies and myxoid stroma), myxomatous, sarcomatoid, hepatoid, and parietal variants.It is characterized by a glandular pattern; frequently there are intracytoplasmic or extracytoplasmic eosinophilic, PAS+ round hyaline bodies or globules. IHC for cytokeratins and AFP.  pure YST part of a mixed germ cell tumor Localizations : it most often occurs in the testis (orchioblastoma), but is also seen in the ovary and some extragonadal sites (prostate, sacrococcygeal region, pericardium, pineal gland, urachus, liver, uterus)  Therapy : cisplatin-based chemotherapy alone is an alternative to laminectomy or radiation therapy in the management of epidural cord compression from EST, even when the cord compression is severe.  immature, malignant or solid teratoma (IT) / teratoblastoma / dysembryoma / organoid or teratoid tumor : a solid tumor resembling a dermoid cyst but composed of immature embryonal and/or extraembryonal elements derived from all 3 germ layers Symptoms & signs : growing teratoma syndrome (GTS) Localizations :  in children : ovary (45%), sacrococcygeal region (40%, causing dystocia; Middeldorpf or tailgut tumor : Middeldorpf V. Zur Kenntnis der Angebornen Sacral-Geschwulste. Virchows Arch (Pathol.Anat.) 101:37-41 (1885). This term is no longer used becauseit lacks specificity), testes, retroperitoneum, mediastinum (=>respiratory distress) , nasopharynx, intracranium, neck and stomach in adults : in the ovary or testis Laboratory examinations : tumor markers : AFP+ref in epithelial cells of primitive cysts, adenoid and gut-like structures of probably entodermal origin; b-hCG Therapy : surgery followed by vincristine + chemotherapy (AMD, cyclophosphamide, methotrexate, bleomycin) teratoma with malignant transformation (MT) is a well-described entity that refers to the MT of a somatic teratomatous component in a GCT to a histology that is identical to a somatic malignancy (carcinoma or sarcoma, eg, primitive neuroectodermal tumors, undifferentiated rhabdomyosarcoma, anaplastic small-cell tumor, adenocarcinoma, and leukemia) Therapy : surgical resection has been the mainstay of therapy for localized transformed disease because these tumors are thought to be resistant to standard treatment. Chemotherapy for MT limited to a single cell type may result in major responses and long-term survival in selected patients. Local therapy after chemotherapy is an important component of treatment to achieve maximum response.  spermatocytic seminoma (SS) / spermatocytoma (10%) : clean background, low mitotic rate, areas (10-30% of the tumor) in which the 3 cell types characteristic of conventional spermatocytic seminoma can be identified under light microscopy, absence of lymphocytes, low tendency to metastasize, diploid or polyploid > aneuploid, c-kit+/- (derived from spermatogonia or primary spermatocytes but 40% of the SSs originate from primordial cells), PLAP-, NY-ESO-1+ spermatocytic seminoma associated with a sarcomatous component, sometimes rhabdomyosarcomatous type : the presence of the sarcomatous elements transformed the usually innocuous spermatocytic seminoma into a highly aggressive neoplasm. The sarcomatous elements may represent a nonseminomatous germ cell component germinoma / gonocytomas (gonocyte is the primitive reproductive cell of the embryo or a secondary gamete-producing cell) : a type of GCT consisting of large round cells with vesicular nuclei, usually found in the ovary, undescended testis, anterior mediastinum, or pineal gland. All are characterized by isochromosome 12p : the (dysplastic) gonocytes from which these tumours are derived are prone to polyploidization, especially in the gonads seminoma / spermatocytoma / spermocytoma / seminomatous germ cell tumor : a radiosensitive, malignant neoplasm of the testis, a type of GCT thought to be derived from the sexually undifferentiated embryonic gonad; they retain their gonocyte characteristics and the single gonocytes have little or no stem cell potential.; 3 histologic variants are recognized testicular carcinoma in situ (CIS) / intra-tubular germ cell of neoplasia of the unclassified type => testicular seminomas; problematic variants include seminomas with tubular, granulomatous, and edematous patterns.  classical seminoma (CS) / typical seminoma (TS) / classic pure seminoma (85%) : "tigroid" background, stromal lymphoid infiltrates, retroperitoneal relapse, aneuploid, c-kit+, PLAP+, NY-ESO-1- anaplastic seminoma (AS) (5%) : spermatocytic seminoma with a predominant anaplastic component (nuclei have large rope-like nucleoli with granular and filamentous chromatin). In addition, sheets of cells with vesicular nuclei and prominent nucleoli superficially resembling embryonal carcinoma are found. There are numerous large mononuclear and multinucleated giant cells with bizarre nuclei and prominent nucleoli, but no sarcomatous elements. Many normal and abnormal mitotic figures are present. Tunical and vascular invasion and extensive necrosis are constant features. IHC : p53 overexpression, PLAP-, LCA-, NSE-, AFP-, hCG-, vimentin-, and cytokeratins-. Despite the presence of a major anaplastic component, no patient has developed metastasis. seminoma with syncytiotrophoblastic giant cells (STGC) secretes hCG (a fact that raises serious difficulties in its differential diagnosis with combined seminomas and choriocarcinomas) atypical seminoma teratogenic gonocytoma if the tumour stem cell has differentiation potential; it is an epiblastoma (epiblast is the upper layer of the bilaminar embryonic disc present during the second week; it gives rise to ectoderm except for the neural plate) if no differentiation is manifest, but may differentiate along embryonic lines into teratoma or may show extraembryonic differentiation towards yolk sac tumor or choriocarcinoma dysgerminoma : the most common malignant GCT of the ovary, composed of large round or polygonal cells with much glycogen, which are frequently radiosensitive and located bilaterally Aetiology : mutations in OPCML embryonal carcinoma (EC) : a highly malignant GCT that is a primitive form of carcinoma, probably of primitive embryonal cell derivation; it has a histological appearance similar to that of a yolk sac tumor (43-9F mAb+; PLAP+ in 75% ), producing a-fetoprotein (AFP) in the cytoplasm of single cells in the solid masses and in areas forming tubular patternsref. In females, there is a median age of 15; in males the majority of patients are adolescents or older. It usually occur admixed with other GCT types. The combination of positivity for placental alkaline phosphatase and negativity for epithelial membrane antigen can assist in the distinction of embryonal carcinomas from somatic carcinomas. pure EC part of a mixed germ cell tumor some types of choriocarcinoma combined or mixed GCTs : AFP+ structures could be interpreted as early stages of embryonal developmentref.  teratocarcinoma : consisting of elements of teratoma with those of embryonal carcinoma or choriocarcinoma, or both Localizations : occurring most often in the testis. polyembryoma : a rare, immature GCT characterized by numerous AFP+refembryoid bodies in association with mature and immature teratoma structures (extraembryonic differentiation) and primitive embryonic tissue, usually found in the ovary => retroperitoneum) and testis. AFP+ not only in yolk sac cells among the embryoid bodies, in the endoderm and in the margins of the ectodermal cells, but also in multiple elements in the mucinous matrix. Hepatoid tissues react positively to AFP and alpha antitrypsin (AAT) as well as to hCG. By using hCG and human placental lactogen (hPL) as markers it is proven that among trophoblastic cells of the tumor, not only syncytiotrophoblastic cells but also the intermediate cells and the cytotrophoblastic cells could be identifiedref. Many tumors are mixtures of types.  embryoid bodies : structures resembling embryos, occurring in several types of GCTs.  Hepatic tissue is observed in 9.3% of GCTs. The incidence of hepatic tissue is low in tumors of the ovary (5%), high in both retroperitoneal (27%) and sacro-coccygeal (24%) tumors, and low in both mature (0.3%) and immature teratomas (11%). It is usually encountered in infancy, and the frequency is high in both yolk sac tumors (48%) and mixed GCTs (52%). The hepatic tissue found mainly in mature or immature grade 1 teratomas was similar to adult normal human liver tissue (Ha-type). Tissue in areas consisting of some immature somatic elements of a mixed GCT is similar to embryonic or fetal liver tissue (Hf-type). Many hepatic nests found in a polyembryoma are of both Ha- and Hf-types. The hepatic tissue found in close relation to yolk sac elements shows predominantly hepatocellular carcinoma-like features (HCLS). Immunohistochemically, the cytoplasm of adult liver-type cells is positive for a1-antitrypsin (AAT), human albumin (ALB), and the third (C3) and fourth (C4) components of the complement system. The cytoplasm of fetal liver-type cells shows the same positivity; in addition, these cells are positive for a-fetoprotein (AFP) in 25% of the cases. The cytoplasm of hepatic cells of HCLS was positive for AFP, AAT, ALB, C3, and C4. A weakly positive reaction for CEA and CA19-9 is observed in bile duct-like structure in some Hf-type casesref.
melanocytoma : a neoplasm or hamartoma composed of melanocytes (malignant) melanoma (MM) / melanotic cancer or carcinoma / melanoblastoma / melanocarcinoma (1.5%) : a malignant neoplasm of melanocytes, characterized by irregular borders and dyshomogeneous color (also achromic areas) and cytological atypias Epidemiology : > 100,000 new cases of melanoma are diagnosed every year and the numbers are rising; 30,000 deaths every year worldwide  Pathological types :  superficial spreading melanoma (SMM) : the most common type of MM, characterized by a period of radial growth atypical of melanocytes in all layers of the epidermis (Paget's cell / pagetoid cell (a large, irregularly shaped, pale anaplastic tumor cell with vacuolated cytoplasm and a vesicular nucleus that is usually hyperchromatic and surrounded by a clear zone; cells occur singly or in small clusters in the epidermis)) which do not undergo neurotization, usually associated with regional lymphadenitis and a lymphocytic cellular host response that is sometimes accompanied by partial or complete regression of the radial growth phase (RGP); deeply invasive growth (vertical growth phase (VGP)) is superimposed on the radial phase. It occurs most often on the lower leg or back, usually presenting as a small pigmented macule to a slightly palpable flat lesion that assumes an irregular outline on enlargement. While RGP melanoma cells remain dependent on exogenous growth factors supplied by surrounding keratinocytes, are incapable of anchorage-independent growth, are not tumorigenic in immmunodeficient mice and do not metastatize in patients, VGP melanoma cells acquire growth-factor and anchorage-independent growth, are tumorigenic in animals and are highly metastatic both in patients and in experimental animal models. Allen-Spitz melanoma : juvenile melanoma, a poorly pigmented lesion composed of plump spindle and/or epitheloid cells, some perhaps multinucleated with large nuclei, often with prominent nucleoli and mitosis. Is now considered malignant melanoma, type superficial spreading (Allen A & Spitz S. Compound blue nevi. Cancer 6:1-6 (1953)) nodular melanoma : a type of MM arising without a perceptible radial growth phase, most often occurring on the head, neck, and trunk, typically presenting as a uniformly pigmented, elevated, bizarrely colored nodule that enlarges rather rapidly and commonly ulcerates, which may arise de novo or from a preexisting malignant melanoma of a different type. acral-lentiginous melanoma: an uncommon type of MM, although it is the most common type seen in nonwhite individuals, occurring chiefly on the palms and soles, especially on the distal phalanges of the fingers and toes, often on the tip of the digit or nail fold or bed (subungueal melanoma) sometimes involving mucosal surfaces, such as the vulva or vagina It typically presents as an irregular, enlarging black macule, which has a prolonged noninvasive stage. Histology : conventional MM polypoid MM desmoplastic MM (DMM) Configuration of tumor cells : mixed cell type epitheloid cell type spindle cell type Clarke's classification :  I : many melanosomes of different sizes, melanofilaments II : nuclear anomalies, abortive spheroidal melanosomes type 1 : pigmented melanocytes type 2 : nonpigmented melanocytes (amelanotic melanoma : an unpigmented MM) III : only spherical melanosomes (commonest type) granular matrix, partially melanotic lamellar IV : granular or lamellar organelles, many mitochondria Onset :  sporadic melanomas (90%) : 0.2-2% have germline mutations in CDKN2A. Some have somatic mutations that exclusively affect the ARF-coding sequence in the shared exon 2 or ARF-specific exon 1b deletion activating Tyr-HRAS mutations absence or very low incidence of point mutation or allelic loss of TP53 Myc amplification and overexpression activating NRAS mutations in 56% of congenital nevi, 33% of primary melanomas and 26% of metastatic melanoma, rarely in dysplastic nevi, suggesting a distinct evolutionary path to melanoma familial melanomas (10%) : 25-40% have inactivating mutations in CDKN2A (it contains 2 upstream exons, 1a and 1b, driven by separate promoters, which result in alternative transcripts that share common downstream exons 2 and 3 : although a common acceptor site in the second exon is used by both first exons, the ORFs remain distinct in the shared exon 2) : some specifically target exon 1a which codes for INK4A / p16 exclusively (it inhibits CDK4/CDK6-mediated phosphorylation and inactivation of RB1), others p14 / ARF (it inhibits MDM2-mediated ubiquitylation and subsequent degradation of p53). On the contrary INK4B inactivation is not significant : as INK4A is lost in almost all established melanoma cell lines, but in only 15-28% of primary uncultured sporadic melanoma samples, one possible cancer-relevant distinction between INK4A and INK4B might relate to the capacity of INK4A to regulate cellular senescence. 95% of these also have activating NRASmutations, compared with only 10% of those with no family history. The lifetime penetrance (by age 80 years) is 67% overall, but only 58% in Europe, compared with 91% in Australia and 76% in USA, paralleling the baseline population incidences of melanoma for these regions, which is influenced by the amount of UV-light exposure. CDK4 Arg24Cys or Arg24His mutations are epistatic to INK4A inactivation multiple benign or dysplastic nevi (moles) red hair colour (RHC) phenotype : red hair, a fair complexion, the inability to tan and a tendency to freckle, associated with MC1R Arg151Cys, Arg160Trp and Asp294His variatns, which increase the amount of pheomelanin in skin => diminished UV-light protective capacity, increased production of mutagenic and cytotoxic metabolites, and additional pigmentary-independet effect(s) on melanoma risk. The presence of a single MC1R variant increases the penetrance of CDKN2A mutation from 50% to 84%. HGF / SF-HGF-R activation stimulates proliferation and motility of melanocytes by disrupting adhesion between melanocytes and keratinocytes via downregulation of E-cadherin and desmoglein-1 ("scattering"). 10q LOH (30-50%) : PTEN (in 5-15% of uncultured melanoma specimens and metastases, as well as in 30-40% of established melanoma cell lines) the MYC antagonist MXI1 mutations in BRAF (60% of melanomas, activating V599E mutation (also present in 82% of nevi) in 80% of cases) MITF (20%) : up to 13 copies Tumour-associated antigens Pathogenesis : the expression pattern of Slug, a master regulator of neural crest cell specification and migration, correlates with those of other genes that are important for neural crest cell migrations during development. Moreover, Slug is required for the metastasis of the transformed melanoma cells. These findings indicate that melanocyte-specific factors present before neoplastic transformation can have a pivotal role in governing melanoma progressionref Metastases : cancer cells express high levels of CXCR4 (up-regulated thanks to positive selection exercted by hypoxia on tumour cell clones lacking inhibition of the VHL tumour suppressor over HIF-1a), CCR7, and CCR10, and are characterized by a distinct metastatic pattern involving the regional lymph nodes, skin, bone marrow, lung and liver, ie tissues that express peak levels of the ligand chemokines CXCL12 and CCL21 : signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses.  Localizations :  cutaneous melanoma (CM) (99%) mucosal melanoma (MuMs) (1%) : on a mucous membrane (50% are mucosal melanomas of the head and neck (MMHN), accounting for approximately 0.2% of all melanomas), usually in older women; most are acral-lentiginous, but nodular and superficial spreading melanomas also occur Epidemiology : incidence is 0.4 cases per million in USA in stratified squamous mucosa gastrointestinal melanomas oral cavity mucosal melanoma (ORMM) pharyngotonsillar melanoma esophageal melanoma anal melanoma female genital tract, melanomas vaginal melanoma vulvar melanoma leptomeningeal melanoma (LMM) in pseudostratified sinonasal respiratory mucosa upper airway tract (1% of the total melanomas of the head and neck) : sinonasal mucosal melanomas (SNMM) are frequently thicker (median thickness, 9 vs 2.6 mm), polypoid (29 vs none), ulcerated (57 vs 20), and necrotic (57 vs 14) than oral melanoma (P <.001); they demonstrate aggressive morphologic features significantly more frequently than oral melanomas; however, prognosis remains similar in both groups. nasal cavity melanoma paranasal sinus melanoma eustachian tube melanoma ocular melanoma (OM) [eyelid melanoma is a cutaneous melanoma] intraocular malignant melanomas orbit melanoma conjunctival melanoma retinal melanoma uveal melanoma (10% of all melanomas; responsible for approximately 13% of melanoma deaths) Epidemiology : equal gender distribution and with a peak incidence in the age range 60-80 years. In consequence of their hidden location, they are usually diagnosed in a locoregionally advanced clinical stage, with a rate of 5-48% of regional and 4-14% of distant dissemination.  Prognosis : far more aggressive behaviour than that of skin melanomas; 5-year actual survival rates are poor (17-48%), which is attributed mainly to a haematogenous dissemination  Therapy : earlier reports advocated radical surgery as the mainstay of therapy; however, local recurrence and survival were unchanged whether radical surgery or local excision was performed, and the most recent data are favoring the conservative approach when appropriate. Unfortunately, a multitude of adjuvant therapies have been tried without any success. Adjuvant radiotherapy plays a role when combined with surgery, particularly in the head and neck region and female genitalia, but this is reserved for nodal and locoregionally advanced disease and has had no effect when used as a prophylactic method. Local control with either surgery or radiotherapy is frequently (60-70%) achieved, but the rates of local, regional and distant recurrences are high (50-90%, 20-60% and 30-70%, respectively).  melanomatosis : the formation of melanomas in various parts of the body. Laboratory examinations : IHC for S-100 protein, tyrosinase, HMB-45, melan A, and microphthalmia transcription factor cancer thickness : thicker melanomas are more likely to spread than thinner ones, but thin cancers sometimes spread too, and only 40% of thick melanomas spread Breslow's thickness : maximal thickness of a primary cutaneous melanoma measured in tissue sections from the top of the epidermal granular layer, or from the ulcer base (if the tumour is ulcerated), to the bottom of the tumour, as assessed with micrometric oculars; metastatic rates correlate closely with tumour thicknessref. Clark's level or thickness (Clark WH. A classification of malignant melanoma in man correlated with histogenesis and biological behaviour. Adv.Biol.Skin 8:621-647 (1967)) : the level of invasion of primary malignant melanoma of the skin. The prognosis is worse with each successive deeper level of invasion. I : limited to the epidermis II : into the underlying papillary dermis (< 0.76 mm) III : to the junction of the papillary and reticular dermis (0.76-1.5 mm) IV : into the reticular dermis (1.5-4 mm) V : into the subcutaneous fat (> 4 mm) lymphatic density (LD) and lymphatic invasion ref : > 12 lymph vessels / mm2 => secondary tumours < 5 lymph vessels / mm2 => cancer does not spread Therapy : chemotherapy : thalidomide in combination with low dose temozolomide has generated favorable results in a phase II investigation as an oral regimen for patients with advanced-stage metastatic melanoma whose disease has not metastasized to their brains augmerosen combined with dacarbazine raises the median survival time to 9.1 months from 7.9 months for patients treated with dacarbazine alone. For patients treated per protocol, who had completed a minimum follow-up time of 12 months, Genasense resulted in a median survival of 10.1 months, compared with 8.1 months for dacarbazine alone. immunotherapy : IL-2 : high numbers of tumour-associated CD64+ macrophages in tumour biopsies were statistically significantly associated with poor response to treatmentref high-dose adjuvant intravenous IFN-a2b for all patients with intermediate- and high-risk melanoma after resection : the substantial toxicity of the therapy and the fact that its benefit is limited to 20-30% of patients at risk have hindered its general acceptance. During treatment the median relapse-free survival was 16.0 months among patients without autoimmunity (antithyroid, antinuclear, anti-DNA, and anticardiolipin autoantibodies, and patients were examined for vitiligo) (108 of 148 had a relapse) and was not reached among patients with autoimmunity (7 of 52 had a relapse). The median survival was 37.6 months among patients without autoimmunity (80 of 148 died) and was not reached among patients with autoimmunity (2 of 52 died). In univariate and multivariate regression analyses, autoimmunity was an independent prognostic marker for improved relapse-free survival and overall survival (P<0.001)ref. Because autoimmunity was observed only after a median of three months — and in some instances, more than a year — from the start of IFN-a2b therapy, the development of autoimmunity cannot be used as a criterion for selecting patients for the therapyref. Nonetheless, patients with a documented preexisting propensity toward autoimmunity might be a group for whom immunotherapy should be considered, providing that the resulting autoimmunity could be anticipated to be managed effectivelyeref.  therapeutic cancer vaccines : Melacine© Canvaxin© Oncophage©. Web resources : Is a Melanoma Vaccine Right for You ? Prognosis : only 35-50% of people with stage III melanoma and 5-10% of those with stage IV disease will achieve long-term survival Web resources :  Melanoma Patients' Information Page Melanoma Research Project Microvascular Research Laboratories
mesothelioma : a tumor derived from mesothelial tissue (mesothelin+) benign or localized fibrous mesothelioma (10%) malignant mesotheliomas (often the result of excessive exposure to asbestos) Epidemiology : about 880 people die of mesothelioma each year throughout Japan Histological subtypes (WHO classification) :  epithelial subtype (55%) : better prognosis when early diagnosed and treated with intrapleural immunotherapy or multimodality therapy tubulopapillary subtype = low-grade mesotheliomas epithelioid subtype = high-grade mesotheliomas malignant mesothelioma with deciduoid features (MMWDF) : MNF116+, HBME-1+, and calretinin+ biphasic subtype (30%) sarcomatoid subtype (15%) Localizations :  pleural mesothelioma (90%) peritoneal mesothelioma (whereas in the 1960s they comprised up to 30% of the total, in recent years the proportion has fallen to about 10% : this changing ratio could also be due to the steady increase in pleural tumors) pericardial mesothelioma (very rare) mesothelioma of testis / mesothelioma of tunica vaginalis (very rare) Aetiology :  environmental carcinogens (asbestos (80% in the Western World : only a relatively small fraction of those exposed develop malignant mesothelioma) and erionite) : the risk is 9.5 times higher than the national average among people who lived within 500 meters of a now-defunct Kubota Corp. asbestos plant in Amagasaki, Hyogo Prefecture, Japan, and 4.7 times higher than the national average among residents living between 500 meters and 1 km from the plant. viruses (SV40, a DNA tumor virus that preferentially causes mesothelioma in hamsters, has been detected in several human mesotheliomas. The expression of the SV40 T antigen in mesothelioma cells, and not in nearby stromal cells, and the capacity of antisense T-antigen treatment to arrest mesothelioma cell growth in vitro suggest that SV40 contributes to tumor development. The capacity of T-antigen to bind and inhibit cellular p53 and Rb-family proteins in mesothelioma, together with the very high susceptibility of human mesothelial cells to SV40-mediated transformation in vitro, supports a causative role of SV40 in the pathogenesis of mesothelioma. Asbestos appears to increase SV40-mediated transformation of human mesothelial cells in vitro) genetic predisposition (in the villages of Karain and Tuzkoy, in Anatolia, Turkey, 50% of deaths are caused by mesothelioma. Erionite may be a cofactor in these same villages) exposure to ionizing radiations (minor importance) Pathogenesis : p53 mutations are rarely found in mesothelioma; p16, p14ARF, and NF2 mutations/losses are frequent  Treatment : historically, no classes or combinations of agents consistently yielded response rates > 20%.  surgical ablation (most are not candidates) radiotherapy (alone didn't demonstrate any efficacy on the patient survival; most are not candidates) chemotherapy alone didn't demonstrate any efficacy on the patient survival stage I :  a therapeutic approach seems to be neoadjuvant intracavitary treatment using cytokines stages II and III : multimodality protocol combining surgery, radiotherapy and chemotherapy (doxorubicin=> P30 and pemetrexed) has proved to be effective in patients with epithelial subtype, negative margins of resection and negative lymph nodes. germinal epithelial tumors angiomatoid tumour : a small, circumscribed, benign tumour of the genital tract, composed of small glandlike spaces lined by flattened or cuboidal mesothelium-like cells. Between first symptoms of disease and diagnosis of mesothelioma often more than 6 months pass as clinical symptoms are rarely typical  Laboratory examinations :  histopathological distinction between adenocarcinoma and mesothelioma requires TEM and experienced pathologists. tumor markers : CA-125
primitive neuroectodermal tumor (PNET) : proposed name for a heterogeneous group of neoplasms thought to derive from undifferentiated neuroglial cells of the neural crest primitive neuroepithelial tumor / neuroepithelioma : any of several closely related types of highly malignant tumors that develop from elements derived from the neural crest and are seen mainly in children. They compose the majority of the PNETs. Included are : medulloblastoma (the commonest) medulloepithelioma ganglioglioma ependymoblastoma neuroblastoma retinoblastoma melanoma pinealoblastoma spongioblastoma : any tumor containing spongioblasts gliosarcoma spongioblastoma multiforme / glioblastoma multiforme spongioblastoma polare / polar or unipolar spongioblastoma / piloid astrocytoma They occur as :  central PNETs : brain, spinal cord and sympathetic nervous system peripheral PNETs (pPNETs) : epidural spinal, extremities, the pelvis, or the chest wall, seen most often in adolescents and young adults, frequently with widespread metastases Askin's tumor : a malignant small-cell tumor of soft tissue in the thoracopulmonary region in childrenref Ewing's sarcoma family of tumors (ESFT) melanotic neuroectodermal tumor (MNET) of infancy (MNTI) / melanotic progonoma or ameloblastoma / melanoameloblastoma / pigmented ameloblastoma / retinal anlage tumor : a rare benign but locally aggressive, rapidly growing, deeply pigmented tumor consisting of an infiltrating mass of cells arranged in an alveolar pattern. Its source of origin is in dispute, the various theories giving rise to its several names. Maturation of the neural elements (e.g. to ganglionic elements) has been reported only occasionally. Epidemiology : occurring almost exclusively in infants during the first year of life  Localizations :  jaw MNTI (mostly) upper jaw MNTI anterior hard palate lower jaw MNTI epididymal MNTI soft tissues of the arm skull central nervous system MNTI (male/female ratio 3.5; much worse outcome. The average age is 8 years (range 3.5 months to 69 years) with 85% becoming clinically apparent in the first decade of life; 73.7% of the patients reported succumbed to their disease at a mean age of 2.8 years, with a postoperative survival time of just 9 months. Systemic metastases were reported in 9 cases and had mostly spread via cerebrospinal fluid) cerebellar MNTI(mostly) pineal gland MNTI Therapy : conservative excision Tumor markers : NSE Experimental animal models : canine malignant melanoma (CMM) is an aggressive neoplasm that is initially treated with surgery and/or radiation therapy.  Unfortunately, the median survival time (MST) for stage II-III CMM treated with surgery alone is 3-5 months.  Hypofractionated RT and chemotherapy in > 90% stage I CMM results in a MST of only 1 year
neuroendocrine tumours (NT) carcinoid (tumor) / apudoma : a yellow circumscribed tumor (0.5-1 cm) arising from APUD cells low-grade typical carcinoids (TC) intermediate-grade atypical carcinoids (AC) Epidemiology : incidence varies between 0.8 and 1.9/100,000 population.  Localizations :  gastrointestinal carcinoid / argentaffinoma (> 95%; 1.5% of all gastrointestinal tumors) prevalence metastases (tumors < 1 cm metastasize in 2% of cases, tumors 1-2 cm metastasize in 50%, and tumors > 2 cm metastasize in 85%) carcinoid syndrome esophageal carcinoid  rare  20-30%   gastric carcinoid 0.5% 20-30% 6% duodenal carcinoid 0.6% 20-30% 3% pancreatic carcinoid rare 20-30% biliary carcinoid rare 20-30% jejunal carcinoid 2.1% 20-30% ileal carcinoid (including ileal neobladder and ileal conduit) 27.3% 35% 70% appendiceal carcinoid 30-45% 2% 0% colon carcinoid 5% 50% => signet-ring cell adenocarcinoma 0% rectal carcinoid 10-15% 10-15% 0% carcinoid tumor of bronchus / bronchial carcinoid (< 5%) genitourinary carcinoid carcinoid tumor of the kidney ureteral carcinoid carcinoid tumor of the urinary bladder carcinoid tumor of the uterine corpus carcinoid of the uterine cervix carcinoid tumor of the broad ligament carcinoid tumour of the seminal vesicles carcinoid tumor of the testis carcinoid tumour of the spermatic cord Symptoms & signs : asymptomatic (66%) carcinoid syndrome (if from argentaffinoma it is a.k.a. argentaffinoma syndrome) due to excess serotonin levels carcinoid crisis : an episodic attack of the carcinoid syndrome. severe cyanotic flushing of the skin lasting from minutes to days (cutaneous vasodilatatory crises) => neck and skin desquamation sudden systemic arterial hypotension fever bowel obstruction (19%) episodes of watery diarrhoea and abdominal cramps (70%) => malabsorption syndromes and weight loss (16% melena (rare) cirrhosis palpable mass (14%) bronchial asthma attacks (15%) edema hyperkinetic circulation carcinoid heart disease (CHD) constrictive pericarditis carcinoid valvular heart disease (CVHD) (50%, unrelated to disease duration and tumour mass) : high levels of 5-HIAA excretion and plasma ANP were found to be associated with CHD, and the risk of progressive heart disease is higher in patients who receive chemotherapy than in those who do not. No significant relation with TGF-b or FGF has been found gastrointestinal carcinoid => right heart valvulopathies (tricuspid failure and pulmonary stenosis) : no effects on left heart as 5-hydroxytryptophane is destroyed in the lungs. bronchial carcinoid => left heart valvulopathies Rarely carcinoid syndrome develops in patients with noncarcinoid malignant tumors and dermatomyositis Prognosis : 5-year survival varying between 15% and 35%  about 20% present with metastases multiple liver metastases don't worse survival rates, but in some cases heterotopic incretion increases the likelihood to develop carcinoid syndrome as liver catabolism (serotonin is metabolized in the liver by MAO into 5-hydroxyindole acetic acid (5-HIAA)) is bypassed most osseous metastases have been reported from carcinoids of the stomach or rectum the development of second primary malignancies (SPM) in patients with gastrointestinal carcinoid tumors is a well-described phenomenon, with reported rates as high as 55%. There is a predilection for gastrointestinal and genitourinary adenocarcinomas, but a variety of other malignancies have been reported as well. The etiology of this malignant predisposition may be rooted in the tumorigenic properties of the various neuroendocrine peptides elaborated and secreted by neuroendocrine cells. Peptides such as secretin, gastrin, bombesin, cholecystokinin (CCK), and vasoactive intestinal peptide (VIP) are believed to promote the growth of tumor cells. As many as 30 peptides and amines identified in neuroendocrine cells may have similar properties.  Laboratory examinations :  biopsy => histology : firm, gray-yellow, submucosal nodules. They grow through the muscularis mucosa and the bowel wall into the mesentery. Mesenteric invasion provokes an intense fibrotic reaction. If the tumors become large, they may present as intraluminal polypoid masses, and occasionally, they are ulcerated. alveolar or glandular carcinoid : palisade of cells at periphery of nidi, no atypias trabecular or nastriform or gyriform carcinoid : cells arranged in cords Intracytoplasmatic vesicles and vacuoles (resisting to fixation) 100-700 nm with peripheral pale halo, increased volume of RER and SER.  IHC with panneuroendrocine tumor markers (NSE, synaptotagmin, neurophysin, NCAM, keratins AE1 and AE3) and hormones (not all carcinoids secrete hormones) preoperative ultrasound may show a solid, hypoechoic, well-defined margin mass combined with calcification or a cyst. [5-HT, histamine]plasma and [5-hydroxy-indolacetic acid (5-HIAA)]urine. chest X-ray, chest, abdominal and pelvic CT, and octreotide scintigraphy are indicated for assessing metastases (even umbilical metastases) Therapy :  surgical resection is the only curative option surgery can also offer prolonged palliation and is needed to restore bowel transit in obstructive/ischaemic bowel problems adequate palliation of hormone-related symptoms can also be achieved by chemotherapy : streptozotocin (response rate = 33%) 5-fluorouracil (response rate = 26%) cyclophosphamide (response rate = 23%) doxorubicin (response rate = 21%) dacarabazine (response rate = 13%). somatostatin analogues 131I-MIBG radiometabolic therapy (response rate = 70%)  IFN-a formulations (response rate = 20-47%) TACE of liver metastases (response rate = 50%, but is accompanied by significant side effects) Prognosis : median survival = 3.5-8..5 years; unfavorable prognostic factors are glandular or mixed histological type, size > 2 cm, location in anterior intestine, [5-HIAA]urine > 150 mg/die  high-grade neuroendocrine tumours (HGNT) :  large cell neuroendocrine carcinomas (LCNECs) small cell carcinomas (SCCs) oat-cell type carcinoma : the cells are round or elongated and slightly larger than lymphocytes; they have scanty cytoplasm and clump poorly. intermediate cell type combined cell type carcinoma Localizations :  small cell lung carcinoma (SCLC) extrapulmonary small cell carcinoma : pure or mixed with squamous-cell carcinoma genitourinary tract epididymis prostate breast (12 cases reported in worldwide literature) uterine cervix endometrium  kidney (30 cases reported in worldwide literature) bladder (135 cases reported in worldwide literature) parotid esophagus stomach  duodenum  pancreas liver gallbladder colon  larynx  primary left ventricular tumor unknown primary tumor  Therapy : curative surgery or primary combination chemotherapy consisting of etoposide and cisplatin + local-regional adjuvant radiotherapy  Prognosis : median survival for patients with limited disease was 25 months compared to 12 months for patients with extensive disease
small round blue cell tumors (SRBCT) of childhood are a group of tumors that share a common histologic characteristic with H&E staining :  they all appear small, blue (high nuclear-to-cytoplasmic (N/C) ratio with nucleus which stains with hematoxylin) and round, but they are vastly different from each other small cell carcinomas non-Hodgkin's lymphoma (NHL) diffuse large B-cell lymphomas (DLBL) acute lymphoblastic leukemias/lymphomas undifferentiated sarcoma small cell osteosarcomas extraskeletal myxoid chondrosarcomas mesenchymal chondrosarcoma Ewing's sarcoma rhabdomyosarcoma (RMS) malignant rhabdoid tumour (MRT) resembles rhabdomyosarcoma but the tumour cells are very primitive rather than of myogenic origin Epidemiology : found almost exclusively in infants (occasionally diagnosed at or immediately after birth)  Localizations :  primarily in the kidney (malignant rhabdoid tumur of the kidney (MRTK)) it may be found in other parts of the body childhood atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS). Most AT/RTs demonstrate monosomy 22 or deletions of chromosome band 22q11 with alterations of the hSNF5/INI1 gene. The tumor's incidence is still undefined, but it may comprise as high as 1 in 4 primitive CNS tumors in infants. Treatment (surgery, chemotherapy, and radiotherapy) is far from optimal, but there are occasional long-term survivors, especially among older children sites outside of the kidney and CNS (21 cases congenital MRTs have been published in the literature. 18 patients had disseminated disease at diagnosis. The median overall survival time for all patients was 2.0 months (0-24 months). The only patient who survived had a localized tumor at initial diagnosis chest wall, axilla, right elbow, and bone marrow. Chest wall lesion was resected completely. Although the masses in axilla and bone marrow responded rapidly to chemotherapy, the elbow lesion increased in size Laboratory examinations : distinctive light microscopy and immunohistochemical findings  Prognosis : poor (highly lethal)  Merkel cell carcinoma (MCC) nephroblastoma / Wilms' tumor medulloblastoma hepatoblastoma neuroblastoma carcinoid tumors malignant peripheral PNET (pPNET) or peripheral neuroepithelioma desmoplastic small round cell tumor (DSRCT) is an increasingly recognized, high-grade malignant tumor that has a predilection for adolescent males. These polyphenotypic tumors characteristically, but not invariably, arise in intimate association with the serosal membrane of the peritoneal cavity and harbor a signature translocation : t(11;22)(p13,q12). In the paratestis they often involve the surface of the epididymis. Characteristic cytologic features include granular chromatin, smooth to irregular nuclear membranes, nuclear molding, cytoplasmic vacuoles, cytoplasmic densities, pseudorosettes, and metachromatic stroma
mixed tumors : a tumor composed of more than one type of neoplastic tissue	adenoepithelioma : a tumor composed of glandular and epithelial elements.		mucoepidermoid carcinoma : a malignant epithelial tumor of glandular tissue characterized by acini with mucus-producing cells and by the presence of malignant squamous elements; it may occur as a low, intermediate, or high grade malignancy
			carcinosarcoma / biphasic sarcomatoid carcinoma : a malignant tumor composed of carcinomatous and sarcomatous tissues, a differentiation continuum of spindle-cell carcinomas / monophasic sarcomatoid carcinoma
	mesenchymoma : a mixed mesenchymal tumor composed of 2 or more cellular elements not commonly associated, not counting fibrous tissue as one of the elements.	benign mesenchymoma rhabdomyochondroma : striated muscle and cartilaginous elements. rhabdomyomyxoma : striated muscle cell and myxoid elements chondromyoma : myomatous and cartilaginous elements. lipomyohemangioma / angiomyolipoma (AML) : by a mixture of spindle (muscle))cells, adipose tissue, epithelioid cells, and blood vessels Localizations :  renal angiolipoleiomyoma(smooth muscle elements) hepatic angiomyolpioma pancreatic angiomyolipoma cutaneous angiolipoleiomyoma(smooth muscle elements) lipomyoma / myolipoma : fatty and muscle elements	malignant mesenchymoma / mixed cell sarcoma : a sarcoma composed of 2 or more cellular elements (excluding fibrous tissue)  myxoid chondrosarcoma / chondromyxosarcoma : myxoid and cartilaginous elements
		myxoma / colloid, gelatinous or mucous tumor : a benign tumor composed of primitive connective tissue cells and stroma resembling mesenchyme  cystic myxoma / myxocystoma : myxoma with cystic degeneration enchondromatous myxoma : one containing cartilage in the intercellular substance. myxoma fibrosum / myxofibroma : a fibroma containing myxomatous tissue. lipomatous myxoma / lipomyxoma / myxolipoma / lipoma myxomatodes : lipoma with foci of myxomatous degeneration. myxoma sarcomatosum / myxosarcoma : a sarcoma containing myxomatous tissue. vascular myxoma : a myxoma containing many blood vessels angiomyxoma : a chorioangioma containing capillary-like blood vessels; it may extend into the umbilical cord and often contains myxomatous tissue resembling that in the normal cord. Localizations : cutaneous angiomyxoma fibroelastoma : a neoplasm consisting of fibroelastic elements. Localizations : papillary fibroelastoma
collision tumor : an area of mixing of malignant cells from 2 distinct tumors (such as a carcinoma and a sarcoma) that have developed separately but near each other.
desmoid tumor : a fibromatous tumor arising in the musculoaponeurotic tissue, usually of the abdominal wall, and often closely resembling low-grade fibrosarcoma; desmoid tumors are not encapsulated, are locally invasive, and rarely metastasize. The tumor often infiltrates adjacent muscle and has a high incidence of recurrence despite seemingly adequate gross resection. The highest frequency is in women of childbearing age of which over 90% of tumors are abdominal in location. For abdominal wall desmoid tumors, approximately 33% are associated with a previous operation at the tumor site Symptoms & signs : the most frequent presenting symptom is a nontender, palpable abdominal wall mass Laboratory examinations : diagnostic imaging is best carried out by CT or MRI, which delineate the extent of involvement of the layers of the abdominal wall and potential intraperitoneal extension Therapy : initial treatment of abdominal wall desmoid tumors is surgical. Because the margins of the tumor are not easily determined and because the tumor often infiltrates muscle and periosteum, limited margins around the gross tumor frequently result in microscopic tumor at the margin. Recurrence rates for abdominal desmoid tumors vary from 9% to 40%, and recurrence is frequent with inadequate margins. A 5-cm margin of resection is considered adequate with mono bloc resection of rib cage, pubic or iliac bone or involved portions of organs such as bladder to achieve these margins. Reconstruction of the abdominal wall with polypropylene mesh is necessary in most cases. In patients in whom adequate margins of resection are achieved, there is no benefit from adjuvant radiotherapy. Second and third resections after recurrence have been associated with no higher rate of recurrence than primary resection. Radiotherapy alone has achieved local control in desmoid tumor in as many as 100% of tumors treated primarily and 75% of recurrent tumors. Radiation doses at least 60 Gy are considered necessary for consistent control. The large radiation dose risks major damage to adjacent bowel and therefore primary radiation treatment of abdominal wall desmoid tumors has a limited role.

Sarcomas :

• grading :
• G1 : well differentiated
• G2 : moderately differentiated
• G3 : poorly differentiated
• G4 : undifferentiated
• TNM staging
• T1 : <= 5 cm
• T2 : > 5 cm
• Ta : superficial fascial involvement
• Tb : deep fascial involvement
• AJCC stage groupings :

disease stage	grading & staging	5-yr OS
I	A : G1,2; T1a,b; N0; M0	98.8%
	B : G1,2;  T2a; N0; M0
II	A : G1,2; T2b; N0; M0	81.8%
	B : G3,4; T1; N0; M0
	C : G3,4; T2a; N0; M0
III	G3,4; T2b, N0; M0	51.7%
IV	A : any G, any T; N1; M0	< 20%
	B : any G; any T; any N; M1

Other microscopic anatomy descriptive terms :
• adenoid tumour : adenoma, or neoplasm with glandlike spaces.
• hamartoblastoma : a tumor developing from a hamartoma.
• metastatic tumors of unknown primary origin (MTUP)
• metastatic adenocarcinomas of unknown primary origin (MAUP) (60%)
• ...
• pseudotumor / pseudoneoplasm / false tumor
• Symptoms & signs
• Laboratory examinations
• Experimental animal models
• a transgenic mouse strain developing autologous melanomas expressing P1A, a well-characterized murine cancer testis antigen recognized by T cells. To transform melanocytes, the Ras pathway was activated while simultaneously inactivating tumor suppressor Ink4a/Arf, thereby reproducing 2 genetic events frequently observed in human melanoma. The melanomas are induced by s.c. injection of 4-OH-tamoxifen (OHT). By activating a CreER recombinase expressed from a melanocyte-specific promoter, this treatment induces the loss of the conditional Ink4a/Arf gene in melanocytes. Because the CreER gene itself is also flanked by loxP sites, the activation of CreER also induces the deletion of its own coding sequence and thereby allows melanocyte-specific expression of genes H-ras and P1A, which are located downstream on the same transgene. All melanomas induced in those mice with OHT show activation of the Ras pathway and deletion of gene Ink4a/Arf. In addition, these melanomas express P1A and are recognized by P1A-specific T lymphocytes. This model will allow to characterize the interactions between the immune system and naturally occurring tumors and thereby to optimize immunotherapy approaches targeting a defined tumor antigen^ref
Transposons have provided important genetic tools for functional genomic screens in lower eukaryotes but have proven less useful in higher eukaryotes because of their low transposition frequency. Sleeping Beauty (SB), a member of the Tc1/mariner class of transposons, can be mobilized in mouse somatic cells at frequencies high enough to induce embryonic death and cancer in wild-type mice. Tumours are aggressive, with some animals developing two or even three different types of cancer within a few months of birth. The tumours result from SB insertional mutagenesis of cancer genes, thus facilitating the identification of genes and pathways that induce disease. SB transposition can easily be controlled to mutagenize any target tissue and can therefore, in principle, be used to induce many of the cancers affecting humans, including those for which little is known about the aetiology. The uses of SB are also not restricted to the mouse and could potentially be used for forward genetic screens in any higher eukaryote in which transgenesis is possible^ref.
Web resources : Mouse Tumor Biology Database (MTB), founded in 1997 by The Jackson Laboratory, contains data of inbred, hybrid and genetically engineered mouse strains that develop tumours. It also includes results from studies in which mice have been exposed to tumour-promoting conditions, including treatment with chemicals, growth factors and hormones, radiation exposure and viral infection. The information provided in the database includes details of organs and tissues affected, data on tumour frequency and latency, associated genetic factors, tumour pathology images and relevant references. The database can be searched in several ways : by tumour type, for specific strains or for lines carrying genetic aberrations that affect a gene of interest.
 
• Prevention : 33% of current cancers are preventable
• primary prevention
• reduction of aetiological or risk factors
• surgical ablation of predisposed tissues/organs :
• prophylactic thyroidectomy in MEN-IIA
• prophylactic mastectomy and ovariectomy in young women with hereditary risk of breast cancer, especially those with mutations in the gene encoding BRCA1 or BRCA2
• prophylactic bilateral total hysterectomy and salpingo-oophorectomy in women with hereditary non-polyposis colorectal cancer (HNPCC)^ref
• prophylactic partial colectomy in ulcerative colitis with biopsy-proven dysplasia
• cancer chemoprevention
• preventive cancer vaccines
• secondary prevention (screenings)
• 70% of patients have clinically localized disease
• 58% have actually localized disease
• 12% have apparently localized disease (microscopic metastases)
• 30% have clinically disseminated disease
 
• Therapy
• targeted to cancer cells
• surgical cancer ablations (60% of curative treatments)
• cancer radiotherapy (30% of curative treatments; 60-70% of patients during the whole course of the disease)
• cancer chemotherapy (20% of curative treatments)
• cancer chronotherapy takes advantage of the asynchrony that exists in cell proliferation and drug metabolism between normal and malignant tissues (see circadian rhythms) by administering therapy at a specific time of the day. Most conventional cancer therapeutic strategies are aimed primarily at maximizing cytotoxicity and avoiding acquired drug resistance : chronotherapy has been developed to increase the therapeutic index of chemotherapies. The coupling of proliferating rhythm between host and tumour cells is usually observed in slow-growing tumours, although, in these cases, DNA synthesis and mitotic indices are oftenn considerably higher in tumour cells throughout th 24-hour period. The altered circadian rhythms, or ultradian rhythms (< 24-hour oscillation) in cell proliferation are often observed in fast-growing or advanced-stage tumours. Chronotherapy increases survival time of children with ALL by 4.2-fold in a 8-year study, and by 2.6-fold in a 15-year disease-free survival analysis.
• percutaneous ethanol injection (PEI)
• cancer immunotherapy / biological response modifiers (BRM)
• immune system enhancers
• cytokines
• whole tumour cell therapeutic vaccines
• tumour antigen therapeutic vaccines
• anti-cancer monoclonal antibodies
• cancer gene therapy
• replication-selective oncolytic viruses (viral oncolysis)
• thermoablative tumor therapy
• radiofrequency ablation (RFA)
• high-intensity focused ultrasound (HIFU) / focused ultrasound surgery (FUS)
• microwave coagulation therapy (MCT)
• laser-induced thermotherapy (LITT)
• hormonal therapies for hormone-dependent tumors
• surgical hormonal therapy
• hormonal chemotherapies
• anti-hormone therapeutic vaccines
• targeted to cancer microenvironment
• anti-angioneogenic therapies target wild-type vascular endothelial cells, more effective targets as their relative genomic stability makes acquisition of drug resistance less likely. Under most circumstances, however, angiogenesis inhibition appears to be cytostatic rather than cytotoxic, and therefore tumor growth inhibition would probably require prolonged maintenance therapy with the anti-angiogenic agents.
• antiangiogenic chemotherapy
• antiangiogenic radiotherapy
• in vivo anti-angiogenic gene therapy mediated by retroviral vectors
• antiangiogenic monoclonal antibodies
• anti-angiogenetic tumor vaccines
• transcatheter arterial embolization (TAE) : as hepatocellular carcinoma (HCC) (but not liver metastases !) is vascularized 100% from hepatic artery while normal hepatocytes receive 75% of blood flow from portal vein, the hepatic artery or its branches (segmental TAE/TACE) can be selectively embolized via angiographic femoral artery catheterism by using spirals, 5-10 mL of
• styrene maleic acid neocarzinostatin (SMANCS) (Lipiodol (S/L)) microparticles
• polyvinyl alcohol particles (PVA)
• Gelfoam pledgets
• poly-lactide-co-glycolide (Plcg) -microspheres
... which targets the unique vascular architecture of tumor blood vessels, which are hyperpermeable and lack a well-developed lymphatic system, eventually emulsified with chemotherapeuticals (transcatheter arterial chemoembolization (TACE) : embolization also reduces drug washout and increases local concentrations by 80-folds :
• doxorubicin
• epirubicin (50-70 mg)
• mitomycin C)
There is the risk for massive necrosis.
• combined modality therapy / multimodality therapy : treatment of cancer using 2 or more types of therapy, such as cancer radiotherapy, cancer chemotherapy, or surgical cancer ablations in an effort to achieve additive or synergistic effects
• chemoradiotherapy / chemoradiation therapy : cancer chemotherapy + cancer radiotherapy
• neoadjuvant therapy / preoperative therapy / presurgical therapy : initial use of one modality, such as cancer chemotherapy or cancer radiotherapy, to decrease the tumor burden prior to treatment by another modality, usually surgery
It is a common belief that participating in clinical trials leads to a better outcome for patients with cancer, regardless of whether they are assigned to the control or experimental group of the study, but there are little evidences to support this "trial effect" and it should no longer be emphasized as an incentive for patient recruitment. Even though there might be no immediate benefit from participating in a clinical trial, it is important for trial participants to realize the benefit for future patients^ref.
Spontaneous tumour regression occurs when the malignant tissue mass partially or completely disappears without any treatment or as a result of a therapy considered inadequate to influence systemic neoplastic growth, or when the metastases disappear after resection of the primary tumor. This definition makes it clear that the term 'spontaneous regression' applies to neoplasms in which the overall malignant disease is not necessarily cured and to cases where the regression may not be complete or permanent. It is likely due to tumour immunity^ref.
The abscopal effect is characterized by the spontaneous regression of unirradiated tumors resulting from the effect of irradiation on remote tissue.
Spontaneous tumour regression has been reported for :
• neuroectodermal tumors
• melanoma^{ref1, ref2, ref3} : choroid metastases^ref
• neuroblastoma. Spontaneous regression is more common in neuroblastomas (TrkA⁺) than in any other tumor type, especially in young patients under the age of 12 months, especially with stage 4s, despite a large tumour burden (N-myc amplification and chromosome 1p deletion is associated with a poor outcome). Unfortunately, the full clinical spectrum of neuroblastomas also includes very aggressive tumors, unresponsive to multi-modality treatment and accounting for most of the pediatric cancer mortalities under 5 years of age^ref1,
• small cell lung cancer (SCLC) : associated with anti-Hu associated paraneoplastic sensory polyneuropathy^ref
• desmoplastic infantile gangliogliomas (DIGs) : regression of the residual tumors after surgical ablation^ref
• primitive neuroectodermal tumour (PNET) of the kidney : spontaneous regression of pulmonary metastases after nephrectomy^ref
• juvenile-onset recurrent respiratory papillomatosis^ref
• retroperitoneal germ cell tumors (GCT)^ref : retroperitoneal metastases from a primary pure anaplastic seminoma in a a 27-year-old marihuana smoker^ref
• gestational trophoblastic disease (GTD)^ref
• lactating adenoma^ref
• sarcomas
• multicentric and solitary infantile myofibromatosis^ref
• rhabdomyomas associated with tuberous sclerosis^ref
• astrocytomas of the optic disk^ref
• benign cerebellar astrocytomas : regression of residual tumor after resection^ref
• infant semilunar valve myxoma^ref
• metastatic endometrial stromal sarcoma^ref
• hemangiomas
• capillary hemangioma of the optic disc^ref
• congenital subglottic hemangiomas^ref
• infantile haemangioma : rapid growth during the first year of postnatal life, followed by spontaneous regression from 1 to 7 years of age^ref
• infantile hepatic hemangioendothelioma (IHH)^ref
• carcinomas
• renal cell carcinoma (RCC) : pulmonary^ref, pleural^ref, or choroidal^ref metastases spontaneously regressed after nephrectomy or radiofrequency ablation (RFA) of primary tumor. Pretreatment levels of NK cells and T cells predict a response to IL-2 and IFN-a in metastatic RCC (mRCC)^ref
• small cell esophageal carcinoma^ref
• Merkel cell carcinoma (MCC) : there are 5 published cases^{ref1, ref2, ref3}
• hepatocellular carcinoma (HCC)^{ref1, ref2, ref3} : 14 cases in the English literature; psycho-neuro-immunological approach with psychotherapy, the antidepressant fluvoxamine, glycyrrhizinic acid and dehydroepiandrosterone (DHEA)^ref
• colorectal cancers : 2 cases of regression of liver metastases in the English literature^ref
• thymoma : 10 cases in the Japanese literature^ref
• basal cell carcinoma (BCC)^ref
• keratoacanthoma^{ref1, ref2}
• HPV-infected low-grade intraepithelial lesion (LGIEL) : rate increases in parallel with follow-up duration^ref and desquamation of the cervical epithelium or enhancement of a localized reparative immunologic response after vaginal delivery could play an important role in the spontaneous regression of cervical dysplasia in the postpartum period^ref.
• blood cells
• lymphomas
• primary cutaneous CD30⁺ large T-cell lymphoma (CD30⁺ CTCL)^ref : although frequent spontaneous regression may be observed, skin relapses occur frequently. Regression after bilateral oophorectomy due to bilateral ovarian teratoma has been reported^ref
• NK/T-cell lymphoma of the small intestine (abscopal effect)^ref
• MALT lymphoma of the hard palate : accompanied by Sjogren syndrome^ref
• B-cell chronic lymphocytic leukemia^ref : cutaneous involvement^ref
• stage IE large-cell B-cell lymphoma of the uterine cervix^ref
• Hodgkin's disease (stage IIIA lymphocyte predominant and IIB nodular sclerosing^ref)
• stage IE gingival B-cell malignant lymphoma^ref
• intravascular lymphomatosis with massive tumor in the superior sagittal sinus (SSS), which caused sinus thrombosis^ref
• malignant lymphoma of the lumbar vertebra^ref
• primary gastric lymphoma (PGL) is characterized by a long spontaneous natural history, with long lasting spontaneous remissions and recurrences^ref
• spontaneously regressing rat histiocytoma, AK-5^ref
• myelodysplastic syndromes (MDS)^ref
• solitary mastocytoma^ref
Web resources : Focus on a cure for cancer by Michael Chapman
• Prognosis : long-term relapse (after 10-15 from initial recovery) are common for :
• melanoma
• breast carcinomas
• renal cell carcinoma (RCC)
• Collins law : for children, the period of risk for tumor recurrence must be equal to the patients' age at diagnosis plus 9 months. So any patient surviving a period twice that could be considered as cured. In pediatric tumors the law applies very well for a number of them, but not for others^ref
It has been found that among cancer patients, those who are insured live longer than those who are not. It is because those who are insured detect cancer early and receive sufficient treatment through insurance. In South Korea, Kyobo Life Insurance estimated that some 71.8% of policy holders who received insurance due to cancer between 1997 and 1999 lived > 5 years after they got cancer : the number is almost twice as high as the survival rate (41.4%) of Korean cancer patients who lived > 5 years after they were diagnosed with cancer, announced in 2002 by the National Cancer Center. Kyobo explained that policy holders seem to live longer because they can receive sufficient treatment through insurance : the company spent only W22.9 billion paying policy holders with cancer in 1997, but the amount rose by 10 times to W229.9 billion in 2003.
A widespread belief that dying people are able to postpone death until after important dates is simply not true, according to a US study of > 300,000 Ohioans who died of cancer between 1989 and 2000. Using Christmas, Thanksgiving, and the patient's birthday as the 3 "special dates", there is no dip in deaths the week before, and no corresponding peak in the week after^{ref1, ref2}. The myth springs from selective memory. Stories about loved ones who "held on" until after the holidays are more memorable than those about the uncle who slipped away in mid-Nov. People feel pressured to make it to Christmas, and this says that untimely death is not a failure of self-discipline. Death keeps to its own schedule and doesn't show up on your Palm Pilot or Day-Timer. Maybe very few individuals are able, by some unexplained process, to postpone death until it is convenient, but for them not to show up in his study, they would have to make up < 1% of the deaths. That figure could be about right, as seen in specific populations^ref. Cancer patients are not the best place to look for this strange effect, seen most often when looking at those with chronic heart conditions. Unless you can think of a plausible mechanism it's much harder to believe in a phenomenon. The next step would be to find a biomedical mechanism. Cancer was chosen because, unlike cardiac deaths, the rate is generally flat throughout the year. Heart attacks tend to peak in the winter, for reasons no one really understands. However, a quick re-run of his data for chronic cardiac partients doesn't show any postponement pattern either. If the holidays have any effect on mortality at all, it is on those who die suddenly, with little time to hold on or let go. More people die abruptly of a heart attack on Christmas than on any other day^ref. But the culprit is not the stress of too much revelry : rather it is that people delay going to the doctor because they don't want to break the holiday mood.
Web resources : Calculate prognoses for patients with curatively resected cancers (breast, colon, or melanoma) for local-regional treatment alone or local-regional treatment plus adjuvant systemic therapy at Mayo Clinic
• Specific organ cancers may be found in respective sections of Homo sapiens diseases listed by tissue/organ(s) involved.
• eye cancers
• head and neck cancers
• face skin cancers
• upper airway and digestive tract cancer (UADTC)
• nasal cancers
• paranasal sinus cancers
• lip cancers
• oral cavity cancers
• tongue cancers
• salivary gland cancers
• odontogenic cancers
• rhinopharyngeal cancers
• oropharyngeal cancers
• hypopharyngeal cancers
• laryngeal cancers
• supraglottic cancers
• glottic cancers
• subglottic cancers
85-90% are SCC (HNSCC), but also adenocarcinomas (expecially in salivary glands), plasmacytomas, non-Hodgkin's lymphomas, oral cavity mucosal melanoma (ORMM); multicentric in 15-20%.
Common risk factors : age, tobacco smoking and chewing, ethanol. Aesthetic and functional impairment.
Lymphatic drainage to :
• upper lymph nodes (submandibular, jugular or angulomandibular, middle jugular and lower jugular)
• middle lymph nodes (spinal, supraclavear and in front of thyroid)
• lower lymph nodes (parotideal, buccal and retroauricular)
Locoregional disease with relapses.
Laboratory examinations :
• CT and MRI
Therapy :
• limited : conservative surgery or radiotherapy (conventional, brachytherapy or electrons)
• extended :
• demolitive surgery radiotherapy postoperatory radiotherapy +/- chemotherapy
• concomitant radiotherapy and chemotherapy
• radiotherapy + neoadjuvant chemotherapy +/- surgery
• concomitant high-dose radiotherapy + cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck^ref
• breast cancers
• cardiac cancers
• lung cancers
• blood vessels cancers
• lymph vessels cancers
• gastrointestinal cancers
• esophageal cancers (2%)
• gastric cancers
• hepatic cancers
• pancreatic cancers
• intrahepatic bile duct cancers
• extrahepatic bile duct cancers
• gallbladder cancers
• colon cancers
• peritoneal cancers
• rectal cancers
• anal cancers
Laboratory examinations : Broders system : cytoglogic grading system designed to correlate prognosis and histologic image, developed mainly for adenocarcinoma of the gastro-intestinal canal. From well-differentiated (typical) to undifferentiated (atypical) in 4 grades) (Broder AC. The grading of carcinoma. Minnesota Medicine 8:726-730 (1925)).
• myeloproliferative disorders
• lymphomas / leukemias
• skin cancers
• hair cancers
• sebaceous gland cancers
• sweat gland cancers
• central nervous system (CNS) cancers
• peripheral nervous system (PNS) cancers
• skeletal muscle cancers
• smooth muscle cancers
• bone cancers
• endocrine cancers
• adenohypophysis cancers
• thyroid cancers
• parathyroid cancers
• islet cell tumor / nesidioblastoma
• adrenal cortex cancers
• pheochromocytoma
• chemodectoma / nonchromaffin paraganglioma
• pineal gland cancers
• genitourinary cancers
• genital cancers
• ovarian cancers
• uterine corpus cancers
• uterine cervix cancers
• vaginal cancers
• vulvar cancers
• prostate cancers
• testicular cancers
• urinary cancers
• renal cancers (3%)
• bladder cancers
• adipose tissue cancers
• Web resources : 10% of websites offering information on alternative cancer therapies give advice that could harm patients. Up to 55% of the Internet's 600 million users gather medical information from it. Patients with life-threatening diseases, such as cancer, often use the web to seek out alternative therapies, but with over half a million sites offering advice, the quality of that information varies greatly^ref. Shark cartilage was the most recommended alternative cancer 'cure'. A preliminary human study has suggested that Neovastat, a product derived from cartilage, can lengthen the lives of patients with a type of kidney cancer2. But the research needs to be repeated with larger numbers, and the only published clinical study of a shark cartilage treatment for cancer failed to find any positive effects3. Because such preparations have not been scientifically tested, their benefits are questionable and it is possible that they might interact adversely with conventional treatments. Worse still, 3 websites (HEALL, HealthWorld Online and worldwidehealthcenter.net) overtly discouraged patients from using conventional cancer care, such as chemotherapy and radiotherapy. One of the sites also dissuaded its readers from taking doctors' advice. These websites are a risk to cancer patients. Anyway good websites do exist, and the majority of those tested provided useful and reliable information
• Associations and societies (see also Italian associations)
• American Association for Cancer Research (AACR)
• American Cancer Society (ACS)
• American Society of Clinical Oncology (ASCO)
• American Society for Therapeutic Radiology and Oncology (ASTRO)
• Association of Cancer Online Resources (ACOR)
• British Association for Cancer Research (BACR)
• Canadian Cancer Society
• Cancer Research UK (CRC)
• European Economic Interest Grouping "Liaison Network for Cancer" (GEIE-LINC)
• European Organization for Research and Treatment of Cancer (EORTC)
• European Society For Medical Oncology (ESMO)
• Federation of European Cancer Societies (FECS)
• Imperial Cancer Research Fund
• International Union against Cancer (UICC)
• Multinational Association of Supportive Care in Cancer (MASCC)
• National Foundation for Cancer Research (NFCR)
• Society of Urologic Oncology
• Usenet sci.med.diseases.cancer
• Journals
• Cancer Cell International  [free at PubMed Central]
• Journal of the National Cancer Institute (NCI)
• Nature Reviews Cancer
• Nature Clinical Practice : Oncology
• Centers / Institutes / Organizations
• Austin Research Institute (ARI)
• Bandolier
• BC Cancer Agency
• Cancer at CDC
• Cancer-free
• CancerIndex.org
• Cancer Genetics Web
• Cancer Research Institute (CRI)
• Centenary Institute of Cancer Medicine and Cell Biology
• Comprehensive Cancer Center at University of Michigan
• Dana Farber Cancer Institute (DFCI) at Harvard University
• Fred Hutchinson Cancer Research Center (FHCRC) in Washington, USA
• Grid-computing : Cancer Research
• HealthLinks : Oncology by the University of Washington
• John Wayne Cancer Institute
• Lincoln University
• Ludwig Institute for Cancer Research (LICR)
• M.D. Anderson Cancer Center
• MedlinePlus : Cancer
• Medscape Hematology-Oncology
• Memorial Sloan-Kettering Cancer Center (MSKCC)
• NIH
• National Cancer Institute (NCI)
• Atlas of cancer mortality
• Cancer Diagnosis Program
• Cancer.gov
• Types of cancer
• CancerNet
• Search the CancerLit WAIS engine at the University of Bonn, Germany 
  Enter Query: 
• Search the CancerLit gopher at NIH 
  Enter Query: 
• Physician Data Query (PDQ)
• Genomics and bioinformatics group - Laboratory of molecular pharmacology
• Gene Expression Database for the Molecular Pharmacology of Cancer
• ICIC WWW Server
• NCI Frederick
• Center for Cancer Research (CRC)
• Mouse Models of Human Cancers Consortium (MMHCC)
• Research Resources for cancer researchers
• Tissue Array Research Program samples from several types of cancer.
• The Cancer Genome Anatomy Project (CGAP)
• Mitelman Database of Chromosome Aberrations in Cancer
• The Cancer Chromosome Aberration Project (CCAP) at NCBI
• Organisation of European Cancer Institutes (OECI)
• OncoLink at University of Pennsylvania


Enter Query: 
Search Type: Full TextTitle Only Maximum hits: 102550100
• Molecular Genetics and Cell Biology of Cancer
• Medical Oncology
• Radiation Oncology
• Surgical Oncology
Oncology Tools by FDA
Quackwatch
Steve Dunn's CancerGuide
The Cancer Handbook
• Www resources on cancer
The Cancer Research Institute
The CancerWEB Project by the Gray Laboratory, Middlesex, UK
• CancerConferences.com
• News
• Nature cancer update
• Biospace News : cancer
• Cancer Update at Salk Institute
• CancerTrack a source of cancer news that is updated every 15 minutes


 

Cancer news

• Bibliography
• Kufe, Donald W.; Pollock, Raphael E.; Weichselbaum, Ralph R.; Bast, Robert C., Jr.; Gansler, Ted S.; Holland, James F.; Frei III, Emil, editors : Cancer Medicine. 6^th ed. Hamilton (Canada): BC Decker Inc.; © 2003 [free at NCBI BookShelf]
• Nature Insight Cancer in Nature Vol.411 17 May 2001

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