1. Neoplasia lecture3
Dr Heyam Awad
FRCPath
2016

2. Topics to be covered Dysplasia and carcinoma in situ Cancer stem cells
Epidemiology of neoplasia

3. Dysplasia and carcinoma in situ
Dysplasia = from Greek word
Bad or difficult
Formation or division

4. dysplasia Disordered but non-neoplastic proliferation.
Loss of uniformity of individual cells and in their architectural orientation
Expansion of immature cells
Seen mainly in epithelial lesions

5. Disorganized proliferation= polarity lost = arrangement disturbed

6. Dysplasia/ microscopically
Loss of orientation
Pleomorphis
Large cells
Hyperchromatic nuclei
More mitoses than normal
Mitosis in an abnormal location ( normal location is at the basal layers of epithelium… abnormal: mitosis seen in more superficial layers)

7. Dysplasia. Note the intact basement membrane (no invasion)

9. Dysplasia in glandular epithelium

10. Dysplasia divided to mild, moderate and severe according to extent of involvement and degree of nuclear abnormality

11. Although non neoplastic, dysplastic cells can accumulate mutations and transform to malignant lesions.. But not always and not commonly.

13. Carcinoma in situ
Means= severe dysplasia involving the whole thickness of the epithelium

14. Carcinoma in situ

15. Carcinoma in situ is considered a pre-invasive stage of cancer

16. Dysplasia, behavior Non- neoplastic
Dysplastic foci usually seen adjacent to areas of malignant transformation and can predict malignant transformation.
They are precursors of malignancy.
However, mild and moderate dysplasia Can regress if initial insult removed

17. The presence of dysplasia preceding cancer is utilized clinically for screening purposes
Cervical cancer in the majority of cases originates from dysplasia… screening for dysplasia by cervical smear (pap smear) helps to detect these precancerous lesions and treatment to prevent cancer can be offered.
Colon cancer can occur in patients with inflammatory bowel disease.. Again dysplasia preceded invasive cancer… surveillance helps detecting these precancerous lesions.

18. Cancer stem cells
Cancer cells keep growing and proliferating . They are immortal and with limitless proliferative capacity.
So: they must contain cells with stem-like properties.

19. Stem cells are immortal

20. Cancer stem cell hypothesis
It is thought that only a special subset of cells within a tumor has the capacity for self renewal (act as stem cells)
This means that a cancer mass is composed of two types of cells: the “differentiated “ cells that have limited self renewal capacity and stem cells that are immortal and can divide asymmetrically and keep the tumor mass immortal.
SO :TUMOR MASS IS IMMORTAL BUT NOT EVERY TUMOR CELL IS IMMORTAL.

21. Cancer stem cells
Cancer stem cells are essential for tumor persistence… so elimination of these stem cells is important to cure patients
If cancer stem cells not eliminated… tumor is immortal… no cure

23. Problem with cancer stem cells
They resist therapy.
Why? 1. Because of their low rate of cell division . Note: the available chemotherapy targets highly dividing cells
2. because they produce factors that make them resistant to chemo.. Like MDR 1= multiple drug resistance 1

24. MDR1
MDR1 gene encodes a glycoprotein that makes cells resist drugs by several mechanisms, including efflux of the drug and decreased uptake of the drug by the cells…
So as if MDR1 is swiping away the drug from the cancer cells.
MDR1 is expressed in cancer stem cells making them resistant to chemotherapy.

25. Why we are failing to cure cancer
Probably because of the stem cells…
Chemotherapy kills the proliferating mass of tumor leaving the cancer stem cells that can proliferate and cause recurrence and metastasis

27. Origin of cancer stem cells
Can arise from normal tissue stem cells or from differentiated cells transforming to stem cells with ability of self renewal.
Note: do not mix normal tissue stem cells with cancer stem cells…they mean different things!!!!

28. There is evidence that cancer stem cells can originate from tissue stem cells or from differentiated cells
Example: chronic myelogeous leukemia (CML) originates from hematopoietic stem cells, whereas acute myeloid leukemia are derived from differentiated myeloid precursors

30. Cancer epidemiology

31. USA 2010

32. Cancer incidence/USA 2013

33. Notes
In USA .. The leading cause of cancer death in both sexes is lung cancer
In USA the most common cancer in women is breast cancer and in men is prostate cancer

34. NOTES
In men.. Cancer death rates increased in the last decades.. But now started to decline
In women: overall death rate decreased slightly.. Due to decline in cervical cancer, colon and stomach
Lung cancer in women is increased

35. Jordan National cancer registry
According to 2013 stats the most common cancer among Jordanian males is colorectal cancer followed by lung cancer
According to 2013 stats, the most common cancer among Jordanian females is breast followed by colorectal cancer.

36. Cancer in Jordan

37. Five year survival
Five-year absolute survival rates describe the percentage of patients alive five years after the disease is diagnosed.

39. Geographic and environmental factors
Environmental factors are the predominant cause of cancer
Geographic variations in cancer incidence are due to different life styles and to environmental factors
When people move from one geographic area to another, subsequent generations acquire the same risk of cancer development as original population.
Table 5-2 ,page 171 about occupational cancer.. Have a look please.

40. Cancer and age In general , frequency of cancer increases with age.
Why: accumulation of mutation takes time! And immunity declines with aging.
However, cancer occurs in children. It is responsible for 10% of all deaths in children younger than 15 years.
Most common childhood tumors: leukemias, lymphomas, CNS tumors and soft tissue and bone sarcomas.

41. heredity
Some cancers have inherited predisposition., but still the majority of these need environmental factors to develop cancer
Only 5-10% of cancers are inherited
This inheritance is usually indirect and its effect is subtle

42. Autosomal dominant cancer syndromes
Single gene mutations
Typically linked to inheritance of a cancer suppressor gene.
E:g Retinoblastoma.. More will be discussed later

43. Autosomal recessive syndromes
Usually the problem in DNA repair genes
Example: xeroderma pigmentosum… more later!

44. Familial cancers of uncertain inheritance
All common cancer types can occur in familial forms with unclear pattern of inheritance
Familial cancers are characterized by: early age, arise in 2 or more close relatives of the index case, can be multiple and bilateral
Familial cancers are not associated with a specific phenotype. Colon cancer can be sporadic, autosomal dominant inheritance ( associated with polyps) or familial with no previous polyps
Predisposition to cancer in these familial cases is probably dominant but incomplete penetrance or multifactorial inheritance cannot be excluded

45. Genotype may affect the likelihood of developing environmentally induced cancer
Polymorphism in drug metabolizing enzymes affect lung cancer development among smokers
Genome wide association studies GWAS in lung cancer found variants in a nicotine acid receptor being associated with lung cancer…. These variants were associated with number of cigarettes smoked, so they indirectly increase lung cancer risk by increasing nicotine addiction

46. Acquired pre-neoplastic syndromes
= preneoplastic or precancerous lesions
These increase the likelihood of cancer but the majority do not progress to cancer
They are important for screening
Also if removed.. Can help decreasing cancer incidence
They contain genetic mutations found in the cancer arises from them

47. Examples of preneoplastic lesions
Squamous metaplasia and dysplasia of bronchial mucosa in smokers
Endometrial hyperplasia and dysplasia
Leukoplakia
Colonic adenomas

48. Are benign tumors precancerous
In general no
Some have more risk than other, colonic adenomas have increased risk of malignant transformation and risk depending on degree of dysplasia ( high grade dysplasia carries more risk of malignant transformation than low grade dysplasia)