Carcinoma

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Carcinoma
Classification and external resources
Small cell lung cancer - cytology.jpg
Micrograph of a lung primary small cell carcinoma, a type of carcinoma. The clustered cancerous cells consist primarily of nucleus (purple); they have only a scant rim of cytoplasm. The surrounding pale staining, discoid cells are red blood cells. Cytopathology specimen. Field stain.
ICD-O: 8010-8580
MeSH D002277

Carcinoma (from the Greek karkinos, or "crab", and -oma, "growth") is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during embryogenesis.[1] More specifically, a carcinoma is tumor tissue derived from putative epithelial cells whose genome has become altered or damaged to such an extent that the cells become transformed, and begin to exhibit abnormal malignant properties.

Carcinoma of unknown primary (CUP)[edit]

The term carcinoma has also come to encompass malignant tumors composed of transformed cells whose origin or developmental lineage is unknown (see CUP), but that possess certain specific molecular, cellular, and histological characteristics typical of epithelial cells. This may include the production of one or more forms of cytokeratin or other intermediate filaments, intercellular bridge structures, keratin pearls, and/or tissue architectural motifs such as stratification or pseudo-stratification.[2][3]

Pathogenesis of cancer[edit]

Cancer occurs when a single progenitor cell accumulates mutations and other changes in the DNA, histones, and other biochemical compounds that make up the cell's genome. The cell genome controls the structure of the cell's biochemical components, the biochemical reactions that occur within the cell, and the biological interactions of that cell with other cells. Certain combinations of mutations in the given progenitor cell ultimately result in that cell (also called a cancer stem cell) displaying a number of abnormal, malignant cellular properties that, when taken together, are considered characteristic of cancer, including:

  • the ability to continue to divide perpetually, producing an exponentially (or near-exponentially) increasing number of new malignant cancerous "daughter cells" (uncontrolled mitosis);
  • the ability to penetrate normal body surfaces and barriers, and to bore into or through nearby body structures and tissues (local invasiveness);
  • the ability to spread to other sites within the body (metastasize) by penetrating or entering into the lymphatic vessels (regional metastasis) and/or the blood vessels (distant metastasis).[4]

If this process of continuous growth, local invasion, and regional and distant metastasis is not halted via a combination of stimulation of immunological defenses and medical treatment interventions, the end result is that the host suffers a continuously increasing burden of tumor cells throughout the body. Eventually, the tumor burden increasingly interferes with normal biochemical functions carried out by the host's organs, and death ultimately ensues.

Pathogenesis of carcinoma[edit]

Carcinoma is but one form of cancer - one composed of cells that have developed the cytological appearance, histological architecture, or molecular characteristics of epithelial cells.[2][3] A progenitor carcinoma stem cell can be formed from any of a number of oncogenic combinations of mutations in a totipotent cell,[citation needed] a multipotent cell,[citation needed] or a mature differentiated cell.[citation needed]

Epidemiology of carcinoma[edit]

  • Demography (Age, Race, Sex, etc.)

While cancer is generally considered a disease of old age, children can also develop cancer.[5] In contrast to adults, carcinomas are exceptionally rare in children.[citation needed].

Ovarian carcinoma is most prevelent in middle-age women who became sexually active at a young age.[6]

  • Causes

Smoking, environment, etc.

Carcinoma In situ[edit]

The term carcinoma in situ (or CIS) refers to a small, localized carcinoma that has not yet invaded through the epithelial basement membrane delimiting the carcinomatous cells from adjacent normal cells. CIS is a pre-invasive cancer, and not a pre-malignant entity.[7]

Nearly all cases of CIS will continue to grow and progress until they begin to infiltrate and penetrate into and through the basal membrane or other/adjacent structures. Once invasion occurs, they are no longer considered CIS lesions, but truly invasive carcinomas. If the lesion can be completely removed via surgical resection, cryotherapy, laser ablation, or some other locally-targeted treatment modality before frank invasion and metastasis develops, cure rates for CIS approach 100%.

In some cases, CIS lesions may gradually re-assume more normal-looking cytological and histological characteristics, thereby becoming lower-grade neoplasms. Biologically, this can very often result in less aggressive, slower-growing neoplasms. Indeed, the appearance of the component cells and local tissue architecture at the local site of the CIS may eventually normalize to the point where the transformed cells no longer meet the consensus requirements necessary for it to be classified as a carcinoma. Therefore, this abnormality would no longer qualify as a true cancer.

These changes are also usually accompanied by decreases in surface area and/or volume of the abnormal area. In some not-insignificant proportion of cases, the abnormal cells/tissue may disappear entirely, with the resulting local area containing only normal-appearing tissue. The process is often referred to by oncologists and pathologists as regression of the CIS lesion. Regression of CIS effectively results in the progressive conversion of a malignant neoplasm to a benign one, to a localized area of normal or near-normal tissue, with or without associated scar tissue, which often forms secondary to apoptosis, necrosis, and fibrosis.

Regression is most often manifested after exposure to prolonged changes in the quality and intensity of environmental and/or immunological stimuli.

A very common example is the regression in some lesions of CIS located in the main central and segmental bronchi of the lung. Many pre-invasive lesions in cases of squamous cell carcinoma often regress after long-term reduced exposure of the affected cells and tissues to the original environmental carcinogenic stimulus, such as that seen after long-term abstention from tobacco smoking.[8] Another relatively common example is the immunologically-driven clearing of Human Papilloma Virus HPV from transformed epithelial cells of the uterine cervix, which results in regression of cervical CIS lesions.

Classification of carcinomas[edit]

Malignant neoplasms are exceptionally heterogeneous entities, reflecting the wide variety, intensity, and potency of various carcinogenic promoters.[9]

To date, no simple and comprehensive method for classifying them has yet been devised and accepted within the scientific community.[3]

Traditionally, however, malignancies have generally been classified into various taxa using a combination of criteria, including:[2]

One commonly used classification scheme classifies these major cancer types on the basis of cell genesis, specifically:

  1. Their (putative) cell (or cells) of origin
    1. Epithelial cells => carcinoma
    2. Non-hematopoietic mesenchymal cells => sarcoma
    3. Hematopoietic cells
      1. bone marrow-derived cells that normally mature in the bloodstream => Leukemia
      2. bone marrow-derived cells that normally mature in the lymphatic system => Lymphoma
    4. Germ cells => Germinoma

Other criteria that play a role in a cancer diagnosis include:

  • The degree to which the malignant cells resemble their normal, untransformed counterparts
  • the appearance of the local tissue and stromal architecture
  • the anatomical location from which tumors arise
  • genetic, epigenetic, and molecular features

Histological types and variants of carcinoma[edit]

Adenocarcinoma
(adeno = gland) Refers to a carcinoma featuring microscopic glandular-related tissue cytology, tissue architecture, and/or gland-related molecular products, e.g., mucin.
Squamous cell carcinoma
Refers to a carcinoma with observable features and characteristics indicative of squamous differentiation (intercellular bridges, keratinization, squamous pearls).
Adenosquamous carcinoma
Refers to a mixed tumor containing both adenocarcinoma and squamous cell carcinoma, wherein each of these cell types comprise at least 10% of the tumor volume.
Anaplastic carcinoma
Refers to a heterogeneous group of high-grade carcinomas that feature cells lacking distinct histological or cytological evidence of any of the more specifically differentiated neoplasms. These tumors are referred to as Anaplastic or Undifferentiated carcinomas.
Large cell carcinoma
Composed of large, monotonous rounded or overtly polygonal-shaped cells with abundant cytoplasm.
Small cell carcinoma
Cells are usually round and are less than approximately 3 times the diameter of a resting lymphocyte and little evident cytoplasm. Occasionally, small cell malignancies may themselves have significant components of slightly polygonal and/or spindle-shaped cells.[10]

There are a large number of rare subtypes of anaplastic, undifferentiated carcinoma. Some of the more well known include the lesions containing pseudo-sarcomatous components: spindle cell carcinoma (containing elongated cells resembling connective tissue cancers), giant cell carcinoma (containing huge, bizarre, multinucleated cells), and sarcomatoid carcinoma (mixtures of spindle and giant cell carcinoma). Pleomorphic carcinoma contains spindle cell and/or giant cell components, plus at least a 10% component of cells characteristic of more highly differentiated types (i.e. adenocarcinoma and/or squamous cell carcinoma). Very rarely, tumors may contain individuals components resembling both carcinoma and true sarcoma, including carcinosarcoma and pulmonary blastoma.[10]

Frequent organ sites of carcinoma[edit]

  • Lung: Carcinoma comprises >98% of all lung cancers.
  • Breast: Nearly all breast cancers are ductal carcinoma.
  • Prostate: The most common form of carcinoma of the prostate is adenocarcinoma.
  • Colon and rectum: Nearly all malignancies of the colon and rectum are either adenocarcinoma or squamous cell carcinoma.
  • Pancreas: Pancreatic carcinoma is almost always of the adenocarcinoma type and is highly lethal.
  • Ovaries: One of the most deadly forms due to late detection[11]

Some carcinomas are named for their or the putative cell of origin, (e.g.hepatocellular carcinoma, renal cell carcinoma).

Mutation frequencies in carcinomas[edit]

Whole genome sequencing has established the mutation frequency for whole human genomes. The mutation frequency in the whole genome between generations for humans (parent to child) is about 70 new mutations per generation.[12]

Carcinomas, however, have much higher mutation frequencies. The particular frequency depends on tissue type, whether a mis-match DNA repair deficiency is present, and exposure to DNA damaging agents such as components of tobacco smoke. Tuna and Amos have summarized the mutation frequencies per megabase (Mb) in some carcinomas,[13] as shown in the table (along with the indicated frequencies of mutations per genome).

The high mutation frequencies in carcinomas reflect the genome instability characteristic of cancers.

Mutation frequencies
Cell type Mutation frequency/Mb Mutation frequency per diploid genome
Germline 0.023 70
Prostate cancer 0.9 5,400
Colorectal carcinoma ~5 ~30,000
Microsatellite stable (MSS) colon cancer 2.8 16,800
Microsatellite instable (MSI) colon cancer (mismatch repair deficient) 47 282,000
Hepatocellular carcinoma 4.2 25,200
Breast cancer 1.18-1.66 7,080-9,960
Lung cancer 17.7 106,200
Small cell lung cancer 7.4 44,400
Non-small cell lung cancer (smokers) 10.5 63,000
Non-small cell lung cancer (never-smokers) 0.6 3,600
Lung adenocarcinoma (smokers) 9.8 58,500
Lung adenocarcinoma (never-smokers) 1.7 10,200

Cause of mutations in carcinomas[edit]

The likely major underlying cause of mutations in carcinomas is DNA damage.[14] For example, in the case of lung cancer, DNA damage is caused by agents in exogenous genotoxic tobacco smoke (e.g. acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, acetaldehyde, ethylene oxide and isoprene).[15] Endogenous (metabolically-caused) DNA damage is also very frequent, occurring on average more than 60,000 times a day in the genomes of human cells[14] (also see DNA damage (naturally occurring)). Externally and endogenously caused damages may be converted into mutations by inaccurate translesion synthesis or inaccurate DNA repair (e.g. by non-homologous end joining).

Cause of high frequency of mutations in carcinomas[edit]

The high frequency of mutations in the total genome within carcinomas suggests that, often, an early carcinogenic alteration may be a deficiency in DNA repair. For instance, mutation rates substantially increase (sometimes by 100-fold) in cells defective in DNA mismatch repair[16]

A deficiency in DNA repair, itself, can allow DNA damages to accumulate, and error-prone translesion synthesis past some of those damages may give rise to mutations. In addition, faulty repair of these accumulated DNA damages may give rise to epigenetic alterations or epimutations. While a mutation or epimutation in a DNA repair gene, itself, would not confer a selective advantage, such a repair defect may be carried along as a passenger in a cell when the cell acquires an additional mutation/epimutation that does provide a proliferative advantage. Such cells, with both proliferative advantages and one or more DNA repair defects (causing a very high mutation rate), likely give rise to the high frequency of total genome mutations seen in carcinomas.

DNA repair deficiency in carcinoma[edit]

In somatic cells, deficiencies in DNA repair sometimes arise by mutations in DNA repair genes, but much more often are due to epigenetic reductions in expression of DNA repair genes. Thus, in a sequence of 113 colorectal carcinomas, only four had somatic missense mutations in the DNA repair gene MGMT, while the majority of these cancers had reduced MGMT protein expression due to methylation of the MGMT promoter region.[17] Five reports, listed in the article Epigenetics (see section “DNA repair epigenetics in cancer”) presented evidence that between 40% and 90% of colorectal cancers have reduced MGMT protein expression due to methylation of the MGMT promoter region.

Similarly, for 119 cases of colorectal cancers classified as mismatch repair deficient and lacking DNA repair gene PMS2 expression, PMS2 protein was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 protein expression was deficient because its protein pairing partner MLH1 was repressed due to promoter methylation of the MLH1 gene (PMS2 protein is unstable in the absence of MLH1 protein).[18] The other 10 cases of loss of PMS2 protein expression were likely due to epigenetic overexpression of the microRNA gene, miR-155, which down-regulates the expression of the MLH1 gene.[19]

In the article Epigenetics (see section “DNA repair epigenetics in cancer”), there is a partial listing of deficiencies of expression of DNA repair genes in sporadic cancers due to epigenetic defects. These defects include frequencies of between 13%-100% of epigenetic defects in genes BRCA1, WRN, FANCB, FANCF, MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1 and ATM in cancers including breast, ovarian, colorectal and head and neck carcinomas. Some of these DNA repair deficiencies can be caused by epimutations in microRNAs as summarized in the MicroRNA article section titled miRNA, DNA repair and cancer.

Invasion and metastasis of carcinomas[edit]

The hallmark of a malignant tumor is its tendency to invade and infiltrate local and adjacent structures and, eventually, spread from the site of its origin to non-adjacent regional and distant sites in the body, a process called metastasis. If unchecked, tumor growth and metastasis eventually creates a tumor burden so great that the host succumbs. Carcinoma metastasizes through both the lymph nodes and the blood.

Diagnosis[edit]

Carcinomas can be definitively diagnosed through biopsy, including fine-needle aspiration (FNA), core biopsy, or subtotal removal of single node,.[20] Microscopic examination by a pathologist is then necessary to identify molecular, cellular, or tissue architectural characteristics of epithelial cells.

Types of carcinoma (by ICD-O code)[edit]

Staging[edit]

Staging of carcinoma refers to the process of combining physical/clinical examination, pathological review of cells and tissues, surgical techniques, laboratory tests, and imaging studies in a logical fashion to obtain information about the size of the neoplasm and the extent of its invasion and metastasis.

Carcinomas are usually staged with Roman numerals. In most classifications, Stage I and Stage II carcinomas are confirmed when the tumor has been found to be small and/or to have spread to local structures only. Stage III carcinomas typically have been found to have spread to regional lymph nodes, tissues, and/or organ structures, while Stage IV tumors have already metastasized through the blood to distant sites, tissues, or organs.

In some types of carcinomas, Stage 0 carcinoma has been used to describe carcinoma in situ, and occult carcinomas detectable only via examination of sputum for malignant cells (in lung carcinomas).

In more recent staging systems, substages (a, b, c) are becoming more commonly used to better define groups of patients with similar prognosis or treatment options.

Carcinoma stage is the variable that has been most consistently and tightly linked to the prognosis of the malignancy.

The criteria for staging can differ dramatically based upon the organ system in which the tumor arises. For example, the colon[21] and bladder cancer[22] staging system relies on depth of invasion, staging of breast carcinoma is more dependent on the size of the tumor, and in renal carcinoma, staging is based on both the size of the tumor and the depth of the tumor invasion into the renal sinus. Carcinoma of the lung has a more complicated staging system, taking into account a number of size and anatomic variables.[23]

The UICC/AJCC TNM systems are most often used.[clarification needed][24] For some common tumors, however, classical staging methods (such as the Dukes classification for colon cancer) are still used.

Grading[edit]

Grading of carcinomas refers to the employment of criteria intended to semi-quantify the degree of cellular and tissue maturity seen in the transformed cells relative to the appearance of the normal parent epithelial tissue from which the carcinoma derives.

Grading of carcinoma is most often done after a treating physician and/or surgeon obtains a sample of suspected tumor tissue using surgical resection, needle or surgical biopsy, direct washing or brushing of tumor tissue, sputum cytopathology, etc. A pathologist then examines the tumor and its stroma, perhaps utilizing staining, immunohistochemistry, flow cytometry, or other methods. Finally, the pathologist classifies the tumor semi-quantitatively into one of three or four grades, including:

  • Grade 1, or well differentiated: there is a close, or very close, resemblance to the normal parent tissue, and the tumor cells are easily identified and classified as a particular malignant histological entity;
  • Grade 2, or moderately differentiated: there is considerable resemblance to the parent cells and tissues, but abnormalities can commonly be seen and the more complex features are not particularly well-formed;
  • Grade 3, or poorly differentiated: there is very little resemblance between the malignant tissue and the normal parent tissue, abnormalities are evident, and the more complex architectural features are usually rudimentary or primitive;
  • Grade 4, or undifferentiated carcinoma: these carcinomas bear no significant resemblance to the corresponding parent cells and tissues, with no visible formation of glands, ducts, bridges, stratified layers, keratin pearls, or other notable characteristics consistent with a more highly differentiated neoplasm.

Although there is definite and convincing statistical correlation between carcinoma grade and tumor prognosis for some tumor types and sites of origin, the strength of this association can be highly variable. It may be stated generally, however, that the higher the grade of the lesion, the worse is its prognosis.[25][26]

See also[edit]

References[edit]

  1. ^ "Definition of Carcinoma". Retrieved 27 January 2014. 
  2. ^ a b c Berman JJ (November 2004). "Tumor taxonomy for the developmental lineage classification of neoplasms". BMC Cancer 4: 88. doi:10.1186/1471-2407-4-88. PMC 535937. PMID 15571625. 
  3. ^ a b c Berman JJ (March 2004). "Tumor classification: molecular analysis meets Aristotle". BMC Cancer 4: 10. doi:10.1186/1471-2407-4-10. PMC 415552. PMID 15113444. 
  4. ^ Carcinoma. Academic Press Dictionary of Science and Technology. 
  5. ^ Kuriakose MA, Hicks WL, Loree TR, Yee H (August 2001). "Risk group-based management of differentiated thyroid carcinoma". J R Coll Surg Edinb 46 (4): 216–23. PMID 11523714. 
  6. ^ The Oxford Companion to the Body. Oxford University Press. 
  7. ^ Banerjee AK (April 2009). "Preinvasive lesions of the bronchus". J Thorac Oncol 4 (4): 545–51. doi:10.1097/JTO.0b013e31819667bd. PMID 19279508. 
  8. ^ Ishizumi T, McWilliams A, MacAulay C, Gazdar A, Lam S (March 2010). "Natural history of bronchial preinvasive lesions". Cancer Metastasis Rev. 29 (1): 5–14. doi:10.1007/s10555-010-9214-7. PMC 3417071. PMID 20112052. 
  9. ^ Roggli VL, Vollmer RT, Greenberg SD, McGavran MH, Spjut HJ, Yesner R (June 1985). "Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases". Hum. Pathol. 16 (6): 569–79. doi:10.1016/S0046-8177(85)80106-4. PMID 2987102. 
  10. ^ a b Travis, William D; Brambilla, Elisabeth; Muller-Hermelink, H Konrad; Harris, Curtis C, eds. (2004). Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. World Health Organization Classification of Tumours. Lyon: IARC Press. ISBN 92-832-2418-3. Retrieved 27 January 2014. 
  11. ^ Boyraz; Selcuk; Yazicioglu; Selcuk-Tuncer (September 2013). "Ovarian Carcinoma Associated with endometriosis". European Journal of Obstetrics and Gynecology and Reproductive Biology 170 (1): 211–213. doi:10.1016/j.ejogrb.2013.06.001. PMID 23849309. Retrieved 27 January 2014. 
  12. ^ Roach JC, Glusman G, Smit AF, et al. (April 2010). "Analysis of genetic inheritance in a family quartet by whole-genome sequencing". Science 328 (5978): 636–9. doi:10.1126/science.1186802. PMC 3037280. PMID 20220176. 
  13. ^ Tuna M, Amos CI (November 2013). "Genomic sequencing in cancer". Cancer Lett. 340 (2): 161–70. doi:10.1016/j.canlet.2012.11.004. PMID 23178448. 
  14. ^ a b Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-1114-6, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer
  15. ^ Cunningham FH, Fiebelkorn S, Johnson M, Meredith C. A novel application of the Margin of Exposure approach: segregation of tobacco smoke toxicants. Food Chem Toxicol 2011;49(11) 2921-2933. PMID 21802474
  16. ^ Hegan DC, Narayanan L, Jirik FR, Edelmann W, Liskay RM, Glazer PM (December 2006). "Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6". Carcinogenesis 27 (12): 2402–8. doi:10.1093/carcin/bgl079. PMC 2612936. PMID 16728433. 
  17. ^ Halford S, Rowan A, Sawyer E, Talbot I, Tomlinson I (June 2005). "O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions". Gut 54 (6): 797–802. doi:10.1136/gut.2004.059535. PMC 1774551. PMID 15888787. 
  18. ^ Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers JO, Bannwart F, Yurtsever H, Neuweiler J, Riehle HM, Cattaruzza MS, Heinimann K, Schär P, Jiricny J, Marra G. (2005). Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 128:1160-1171. PMID 15887099
  19. ^ Valeri N, Gasparini P, Fabbri M, Braconi C, Veronese A, Lovat F, Adair B, Vannini I, Fanini F, Bottoni A, Costinean S, Sandhu SK, Nuovo GJ, Alder H, Gafa R, Calore F, Ferracin M, Lanza G, Volinia S, Negrini M, Mcllhatton MA, Amadori D, Fishel R, Croce CM: Modulation of mismatch repair and genomic stability by miR-155. Proc Natl Acad Sci USA 2010, 107:6982-6987. PMID 20351277
  20. ^ Wagman LD (2008). "Principles of Surgical Oncology". In Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ. Cancer Management: A Multidisciplinary Approach (11th ed.). 
  21. ^ Puppa G, Sonzogni A, Colombari R, Pelosi G. TNM staging system of colorectal carcinoma: a critical appraisal of challenging issues. Arch Pathol Lab Med 2010;134:837-52.
  22. ^ Sharir S. Update on clinical and radiological staging and surveillance of bladder cancer. Can J Urol 2006;13(Suppl 1) 71-6.
  23. ^ Pepek JM, Chino JP, Marks LB, D'amico TA, Yoo DS, Onaitis MW, Ready NE, Hubbs JL, Boyd J, Kelsey CR. J Thorac Oncol 2011;6:757-61.
  24. ^ "What is Cancer Staging?". Archived from the original on 2007-10-25. Retrieved 27 January 2014. 
  25. ^ Sun Z, Aubry MC, Deschamps C, Marks RS, Okuno SH, Williams BA, Sugimura H, Pankratz VS, Yang P. Histologic grade is an independent prognostic factor for survival in non-small cell lung cancer: an analysis of 5018 hospital- and 712 population-based cases. J Thorac Cardiovasc Surg 2006;131:1014-20.
  26. ^ "Poorly differentiated carcinoma of unknown primary site". Archived from the original on 2013-12-12. Retrieved 27 January 2014. 

External links[edit]

  • Media related to Carcinoma at Wikimedia Commons