PRECURSORI DI MALIGNITA ’

1. PRECURSORI DI MALIGNITA’

2. STORIA NATURALE DEI TUMORI • LA CANCEROGENESI E’ UN PROCESSO MULTIFASICO • Più eventi sono necessari per la transizione da tessuto normale a tumore maligno

3. Storia Naturale dei Tumori • Eventi più numerosi nel caso di tumori frequenti nell'età adulta/anziana (colon, mammella, polmone,vescica) rispetto a quelli frequenti in età pediatrica (retinoblastoma, leucemie) • Relazione tumori età _______________________________________________________ cellula normale/ lesioni lesioni lesioni lesioni microambiente normale preneoplastiche benigne invasive metastatiche ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ _______________________________________________________ EVENTI GENETICI ED EPIGENETICI

4. Storia Naturale dei Tumori • Eventi più numerosi nel caso di tumori frequenti nell'età adulta/anziana (colon, mammella, polmone,vescica) rispetto a quelli frequenti in età pediatrica (retinoblastoma, leucemie) • Relazione tumori età _______________________________________________________ cellula normale/ lesioni lesioni lesioni lesioni microambiente normale preneoplastiche benigne invasive metastatiche ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ _______________________________________________________ EVENTI GENETICI ED EPIGENETICI

5. Storia Naturale dei Tumori I vari tipi ditumori sono diversi fra loro per quanto riguarda la storia naturale, cioè • insorgenza monoclonale, oligoclonale o policlonale • presenza di lesioni preneoplastiche più o meno definite • numero e tipo di eventi necessari per l’acquisizione della malignità • durata dell’intera storia e delle sue fasi • evoluzione ed aggressività • sedi metastatiche • interazioni con l’ospite Tumori appartenenti a uno stesso tipo istologico e con agente cancerogeno simile presentano generalmente storie naturali simili

6. Progressione • Sequenza di eventi genici e non- che colpiscono una cellula fornendole le competenze per la malignità e la resistenza a terapie _______________________________________________________ cellula normale/ lesioni lesioni lesioni lesioni microambiente normale preneoplastiche benigne invasive metastatiche ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ _______________________________________________________ EVENTI GENETICI ED EPIGENETICI • In una cellula si accumulano attivazione di oncogeni, inattivazione di geni oncosoppressori, e alterazioni di geni coinvolti nella malignità • Implicazioni cliniche :prevenzione, diagnosi precoce, terapia

7. PROGRESSIONE Progressione • Succedersi di alterazioni che conferiscono vantaggio di crescita e/o metastatizzazione. • Origina una progenie di cellule con sempre maggiore malignità. • Anche le terapie esercitano pressione selettiva, • Implicazioni importanti per la terapiaIntervenire prima possibile Combinare terapie appropriate per ridurre lo sviluppo di farmaco resistenza

8. Progressione Modello colon-retto (Modello di Vogelstein e Kinzler) Epitelio normale ↓ ← Inattivazione APC (cr 5) Epitelio iperproliferativo ↓ ← Ipometilazione del DNA Adenoma lievemente atipico ↓ ← Attivazione K-RAS (cr12) Aden. moderatamente atipico ↓ ← Inattivazione di DCC/SMAD4 (cr 18) Adenoma fortemente atipico ↓ ← Inattivazione TP53 (cr 17) Carcinoma ↓ ← Altre alterazioni ? Metastasi

9. Progressione Numero di eventi (hits) • Retinoblastoma 2? • Colon > 7 • Ca polmone 10-20?

10. The process of neoplasia begins with cell transformation. A variety of chemical carcinogens as diverse as benzene, cigarette smoke, and nitrites can initiate and/or promote this process. Radiation, either as low level long-term environmental gamma rays or as higher dose therapeutic radiation, can also produce genetic mutations in cells. Some persistent infectious agents such human papillomavirus can lead to cellular transformation as well. Genetic damage with DNA alterations leads to point mutations of genes, translocations of genetic material between chromosomes, and gene reduplication with amplification. These alterations transform proto-oncogenes into oncogenes. The proto-oncogenes within cells may play a role in growth promotion and regulation in normal cells, perhaps in embryogenesis, but are typically "turned off" in adults. They are "turned on" by transformation and lead to the uncontrolled growth that defines neoplasia.

11. Neoplasia, or uncontrolled cellular proliferation, can result either from mutations that "turn on" the oncogenes that stimulate growth, or from mutations that result in loss of tumor suppressor genes and their products that inhibit cellular growth.

12. Oncogenesis Mechanism Action Example Overexpression of growth factor receptors (such as epidermal growth factor, or EGF)making cells more sensitive to growth stimuli C-erb-B2 ras Increased growth factor signal transduction by an oncogene that lacks the GTPase activity that limits GTP induction of cytoplasmic kinases that drive cell growth Growth promotion Overexpression of a gene product by stimulation from an c-sis oncogene (such as ras) Lack of normal gene regulation through translocation of c-abl a gene where it is controlled by surrounding genes to a place where it is no longer inhibited Loss of normal growth inhibition BRCA-1 Loss of Tumor Suppressor Gene Function Lack of regulation of cell adhesion with loss of growth control APC through cell interaction Loss of down-regulation of growth promoting signal transduction NF1 Loss of regulation of cell cycle activation through sequestation of Rb transcriptional factors Loss of regulation of cell cycle activation through lack of inhibition p53 of cell proliferation that allows DNA repair Limitation of Apoptosis Overexpression of gene, activated by translocation, prevents apoptosis bcl-2

13. Oncogene Associated Neoplasms c-erb-B2 Breast and ovarian carcinomas rasMany carcinomas and leukemias c-sis Gliomas c-ablChronic myelogenous leukemia, acute lymphocytic leukemia c-myc Lymphomas BRCA-1Breast and ovarian carcinomas APC Colonic adenocarcinomas NF-1Neurofibromas and neurofibrosarcomas Rb Retinoblastomas, osteosarcomas, small cell lung carcinomas p53Many carcinomas bcl-2 Chronic lymphocytic leukemia, lymphomas

14. PRECURSORI MORFOLOGICI MACROSCOPICI e MICROSCOPICI di MALIGNITA’ …esempi….

15. UTERO Corpo Utero con iperplasia endometriale

16. Endometrio normale- Fase proliferativa

17. Iperplasia endometriale

20. The first step toward neoplasia is cellular transformation. The chronic irritation from cigarette smoke has led to an exchanging of one type of epithelium (the normal respiratory epithelium at the right) for another (the more resilient squamous epithelium at the left). Thus, there is metaplasia of normal respiratory laryngeal epitheliumto squamous epithelium in response to chronic irritation of smoking. The two forms of cellular transformation that are potentially reversible, but may be steps toward a neoplasm, are: Metaplasia: the exchange of normal epithelium for another type of epithelium. Metaplasia is reversible when the stimulus for it is taken away. Dysplasia: a disordered growth and maturation of an epithelium, which is still reversible if the factors driving it are eliminated.

21. UTERO Cervice Epitelio squamoso cervicale Cervice uterina normale

22. This is the next step toward neoplasia. Here, there is normal cervical squamous epithelium at the left, but dysplastic squamous epithelium at the right. Dysplasia is a disorderly growth of epithelium, but still confined to the epithelium. Dysplasia is still reversible

23. Some epithelia are accessible enough, such as the cervix, that cancer screening can be done by sampling some of the cells and sending them to the laboratory. Here is a cervical Pap smear in which dysplastic cells are present that have much larger and darker nuclei than the normal squamous cells with small nuclei and large amounts of cytoplasm

24. When the entire epithelium is dysplastic and no normal epithelial cells are present, then the process has gone beyond dysplasia and is now neoplasia. If the basement membrane is still intact, as shown here, then the process is called "carcinoma in situ" because the carcinoma is still confined to the epithelium. Neoplastic epithelium is termed carcinoma.

25. MAMMELLA Iperplasia duttale Origina nei dotti terminali intra ed extra lobulari ed è dovuta alla proliferazione delle cellule epiteliali o delle cellule epiteliali e mioepiteliali Iperplasia duttale tipica(IDH) Iperplasia duttale atipica(AIDH)- Rischio x Carcinoma: 4-5 Carcinoma intraduttale(IDCA)

26. AIDH Si manifesta spesso in associazione con la malattia fibrocistica, con le lesioni sclerosanti o con il papilloma

27. Papilloma della mammella • Papilloma solitario  non rappresenta un fattore di rischio • Papillomi multipli  aumentato rischio di sviluppo di carcinoma e possibile associazione con il carcinoma duttale in situ (DCIS) Papillomatosi florida (adenoma) del capezzolo Mostra un’associazione elevata con il carcinoma

28. Stomaco Intestinal metaplasia- associated atypia in a case of chronic atrophic gastritis with intestinal metaplasia. The foveolar epithelium is replaced by intestinal type epithelium with hyperchromatic, elongated and pseudostratified nuclei, atypical cytologic features that appear to be confined to the lower halves of the pits. Note that there is no glandular crowding and that the foveolae, although reactive, are parallel to each other and separated by moderately abundant lamina propria Intestinal metaplasia in chronic autoimmunegastritis. The foveolar epithelium is replaced by intestinal epithelium composedof mucin (goblet) cells and absorbtive columnar cells

29. The immunohistochemical stain for proliferation marker Ki-67 shows normal staining pattern: infrequent labeling of the nuclei in the lower half of the pits

30. Adenocarcinoma gastrico (freccia) e mucosa adiacente non neoplastica Adenocarcinoma gastrico ulcerato e mucosa adiacente con atipie (freccia)

31. a a-Hemigastrectomy specimen, surgery performed for antral adenocarcinoma. The histologic section of gastric mucosa adjacent to the gastric cancer shows non-neoplastic gastric mucosa (right) adjacent to intestinal metaplasia (left). The intestinalized mucosa is composed of irregular, branched foveolae with epithelial buds at the deep aspect, lined by a mucin-depleted epithelium with hyperchromatic nuclei and scattered goblet cells b b-The metaplastic gastric epithelium (left) is contrasted with the non-intestinalized gastric epithelium (right). The nuclei of intestinal metaplasia are elongated, hyperchromatic and pseudostratified. These features appear to involve the surface epithelium focally, finding that is suggestive of low-grade dyspalsia. The nuclei of the normal gastric mucosa (right) although hyperchromatic and elongated, have less crowding and overlapping thant those of the metaplastic epithelium

32. High-grade dysplastic epithelium characterized by low-cuboidal cells with markedly increased N:C ratio, depleted cytoplasmic mucin and enlarged, round nuclei, with loss of nuclear polarity, pseudostratification, and prominent irregular nucleoli Immunohistochemical stain for proliferation marker Ki-67 shows increased nuclear labeling with a predominant upper pit and surface epithelium distribution

33. Colonscopia Intestino normale Polipo- Displasia Adenomatosa

34. Intestino A small adenomatous polyp (tubular adenoma) is seen here. This lesion is called a "tubular adenoma" because of the rounded nature of the neoplastic glands that form it. It has smooth surfaces and is discreet. Such lesions are common in adults. Small ones are virtually always benign. Those larger than 2 cm carry a much greater risk for development of a carcinoma, having collected mutations in APC, DCC, K-ras, and p53 genes over the years.

35. colonoscopic appearance of rectal polyps that proved to be tubular adenomas

36. This small adenomatous polyp (tubular adenoma) on a small stalk is seen microscopically to have more crowded, disorganized glands than the normal underlying colonic mucosa. Goblet cells are less numerous and the cells lining the glands of the polyp have hyperchromatic nuclei. However, it is still well-differentiated and circumscribed, without invasion of the stalk, and is benign

37. This adenomatous polyp has a hemorrhagic surface (which is why they may first be detected with stool occult blood screening) and a long narrow stalk. The size of this polyp--above 2 cm--makes the possibility of malignancy more likely, but this polyp proved to be benign.

38. Here are multiple adenomatous polyps of the cecum. A small portion of terminal ileum appears at the right.

39. This is familial polyposis in which the mucosal surface of the colon is essentially a carpet of small adenomatous polyps. Of course, even though they are small now, there is a 100% risk over time for development of adenocarcinoma, so a total colectomy is done, generally before age 20

40. A microscopic comparison of normal colonic mucosa on the left and that of an adenomatous polyp (tubular adenoma) on the right is seen here. The neoplastic glands are more irregular with darker (hyperchromatic) and more crowded nuclei. This neoplasm is benign and well-differentiated, as it still closely resembles the normal colonic structure.

41. Crypt abscesses are a histologic finding more typical with ulcerative colitis. Unfortunately, not all cases of inflammatory bowel disease can be classified completely in all patients

42. Over time, there is a risk for adenocarcinoma with ulcerative colitis. Here, more normal glands are seen at the left, but the glands at the right demonstrate dysplasia, the first indication that there is a move towards neoplasia

43. Fegato Liver is divided histologically into lobules. The center of the lobule is the central vein. At the periphery of the lobule are portal triads. Functionally, the liver can be divided into three zones, based upon oxygen supply. Zone 1 encircles the portal tracts where the oxygenated blood from hepatic arteries enters. Zone 3 is located around central veins, where oxygenation is poor. Zone 2 is located in between

44. ..displasia su cirrosi… Microscopically with cirrhosis, the regenerative nodules of hepatocytes are surrounded by fibrous connective tissue that bridges between portal tracts. Within this collagenous tissue are scattered lymphocytes as well as a proliferation of bile ducts

45. The malignant cells of this hepatocellular carcinoma (seen mostly on the right) are well differentiated and interdigitate with normal, larger hepatocytes (seen mostly at the left).

46. ..Prostata.. Prostatic intraepithelial neoplasia (PIN), which is dysplasia of the epithelium lining prostate glands, is a probable precursor of prostatic carcinoma. The appearance of PIN may precede carcinoma by 10 or more years. It can be divided into low grade and high grade PIN. Low grade PIN may be found even in men in middle age Compare the normal prostatic gland at the left with the group of acini at the right with prostatic intraepithelial neoplasia (PIN), a precancerous cellular proliferation found in a single acinus or small group of acini.

47. This is prostatic intraepithelial neoplasia (PIN), a precancerous cellular proliferation found in a single acinus or small group of acini. PIN can be low or high grade (as seen here). The finding of PIN suggests that prostatic adenocarcinoma may also be present (about half the time with high grade PIN).

48. At high magnification, this poorly differentiated prostatic adenocarcinoma demonstrates cells with nucleoli and mitotic figures

49. …Cute… Caso n. 1: Donna di 17 anni con neoformazioni pigmentate multiple della cute del dorso; quella indicata dalle frecce, di 0,5 per 0,3 cm. 

50. NEVO DISPLASTICO