Cancers and Neoplasms

Notes
  • Some simple definitions:

_Neoplasm (or tumor): This is an abnormal, new and often rapid and continous growth of cells with the potential of encroaching and damaging of the adjacent structures. There are two types of neoplasms;

 *Benign neoplasms that are often curable

  *Malignant neoplasms – That are also termed as cancers

  • Benign tumors (such as uterine fibroids and skin moles): have well differentiated cells, non-invasive, have low mitotic index, localized with well defined capsules, most of them respond well to treatment but some can grow slowly and large and cause disease because of their sheer size. The do not metastasize.
  • Malignant tumors have cells which are poorly differentiated, are invasive, have high mitotic index, are not capsuled, grow rapidly, may metastasize, are often resistant to treatment and they can recur after removal.
  • Five (5) most common sites of cancer in men (2012): lung, prostate, colorectum, stomach, and liver cancer.
  • Five (5) most common sites of cancer women (2012): breast, colorectum, lung, cervix, and stomach cancer.
  • Dysplasia, often an indication of an early neoplastic process, is an expansion of immature cells (that are restricted to the originating tissue) that is accompanied by decrease in the number and location of mature cells. The detection of these cells is the basis of Papanicolaou (PAP) smear.
  • Neoplasm or cancer in-situ refers to neoplasm or cancer has stayed in the place where it began and has not spread to neighbouring tissues.
  • Cancer that is known to be at the metastatic stage at the time of diagnosis but a primary tumor cannot be identified is termed as “Cancer of unknown primary origin” (CUP) or "occult cancer".
  • Hereditary cancers;

_Less than 0.3% of the population are carriers of a genetic mutation that has a large effect on risk  of cancer and these cause less than 3–10% of cancers.

_Inherited mutations in the genes BRCA1 and BRCA2  increase the risk of breast cancer, ovarian cancer and hereditary nonpolyposis colorectal cancer to values as high as 75%.

  • Roles of hormones in causing cancers include;

_The progression of the sex-related cancers e.g. cancer of the breast, endometrium, prostate, ovary and testis is known to be affected by the levels of specific hormones in the blood.

_Women on hormone replacement therapy (HRT) are more predisposed to developing cancers associated with those hormones than those who are not on HRT.

  • Metastasis of cancers:

_This is the spread of cancer from the original tumour (Primary tumour) to other parts of the body (to form Secondary tumour) and it is the most important prognostic factor.

_Properties of malignant tumours that make them metastasize successfully:

*Ability to break way from the site of their origin.

*Ability to secrete the matrix metalloproteinase enzymes e.g. type IV collagenases that play a key role in tumor cell-mediated extracellular matrix proteolysis.

*Ability to travel in blood or lymphatic system

*Ability to establish in a new site

_Carcinomas tend to metastasize via the lymphatic route of spreading while sarcomas do so more through the hematologic route of spreading.

  • Malignant cancer can spread to almost any tissue of the body though the locations of secondary tumor sites are somehow selective. This selectivity is partly determined by the circulatory anatomy and ability of some tissues to receive metastasized tumours. The selectivity is as follows:

 

Primary

Tumour

The most likely location of  the secondary tumour

GI cancer

Liver

Lung and/or breast

Gray-White junction of the brain

Prostate

Osteoblastic 20 bone cancer

Lung

Osteolytic / osteoblastic 20 bone cancer

Breast

Osteolytic 20 bone cancer

Breast

Lung

 

  • Statistics: global annual incidence of cancers - 14M; global annual mortality rate - 8.2M; annual incidence of cancers in Kenya - 39,000 (of which 60% are below 70 yrs); annual mortality rate in Kenya - 28,000 (3rd highest cause of mortality in Kenya after infectious diseases and cardiovascular diseases); proportion of cancer cases that are diagnosed in late stages in Kenya – 70 to 80%; proportion of cancers caused by the inherited genetic factors – 5 to10%; proportion of cancers caused by radiation - up to 10%; global annual mortality rate due to tobacco - related cancers alone - 20%; contribution of tobacco to the global annual mortality rate from lung cancers - 85%; global annual mortality rate due to HBV, HCV and HPV and other cancer causing viruses -20%; proportion of cancers that is caused by diet and obesity – 30 to 35%; global cancer burden in low and middle income countries (LMICs)-70%; proportion of cancers that are curable if detected early - 30%;   proportion of cancers that are treatable with prolonged survival if detected early - 30%; proportion of cancer patients who can be provided with adequate symptom management and palliative care - 30%.
  • The top 27 cancers globally are as presented below:

 

No

Name of the cancer

%

1.          

Lung

13.0

2.          

Breast

11.9

3.          

Colorectum

9.7

4.          

Prostrate

7.9

5.          

Stomach

6.8

6.          

Liver

5.6

7.          

Cervix uteri

3.7

8.          

Oesophagus

3.2

9.          

Bladder

3.1

10.       

Non-Hodgkin lymphoma

2.7

11.       

Leukaemia

2.5

12.       

Pacreas

2.4

13.       

Kidney

2.4

14.       

Endometrium

2.3

15.       

Lip, oral cavity

2.1

16.       

Thyroid

2.1

17.       

Brain, nervous system

1.8

18.       

Ovary

1.7

19.       

Melanoma of skin

1.6

20.       

Gall bladder

1.3

21.       

Larynx

1.1

22.       

Other pharynx

1.0

23.       

Multiple myeloma

0.8

24.       

Nasopharynx

0.6

25.       

Hodgkin lymphoma

0.5

26.       

Testis

0.4

27.       

Kaposi sarcoma

0.3

28.       

Others

_Vulvar cancer

_Vaginal cancer

 

Source: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F.

  1. Pathogenesis of cancers
  • Molecular basis of cancer pathology
    • The damage of a particular gene is the basis for carcinogenesis
    • It can be caused by either genetic (or DNA) change or epigenetic change (that effects gene expression such as methylation).
    • Gene mutations occur in the cells frequently and cells have the inbuilt mechanisms of detection of these changes and their repairs. When the repair process is not possible, the cell will die through the process of apoptosis (programmed cell death). Failure of the repair mechanisms lead to cancer.
    • In the cell-cycle there are points (checkpoints) where cell replication / reproduction is paused to check for errors.
    • The damaged gene affects the cell-cycle which consists of the following phases:

_G1 phase (or first Gap phase): Cellular contents, a part from chromosomes, duplicate and cell grows in size. The G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis

_S phase (Synthesis phase or DNA replication phase): Each of the 46 chromosomes (or 23 pairs of chromosomes) are duplicated give two sister chromatids.

_G2 phase (or Second Gap phase): The cell checks the duplicated chromosomes for errors make the necessary corrections and the cell gets ready for mitosis. The G2 checkpoint control mechanism ensures that everything is ready to enter the M phase and divide

_M phase (or Mitotic phase): mitosis occurs where the cell separates the copied chromosomes to form two full sets of chromosomes. This phase is further subdivided into prophase, metaphase, anaphase and telophase (PMAT) stages. The cell divides into two new cells (cytokinesis) in telophase stage. The metaphase checkpoint ensures that the cell is ready to complete cell division.

G0 phase (or Quiescent phase): Cells that are not dividing leave the cell cycle and stay in this stage. It is also the beginning of the cell cycle.

Interphase: The gap between G1 and G2 phases.

  • Cyclins and Cyclin-dependent Kinases (CDKs);

_These molecules regulate the cell-cycle.

_CDK requires a partner cyclin to be activated.

_The activated heterodimer contains regulatory subunits of Cyclins and  catalytic subunits of CDKs.

_CDKs act by catalyzing phosphorylation of proteins in the cells. By phosphorylation, proteins are either activated or deactivated.

_CDKs are continuously generated in cells while cyclins are only generated at specific stages of the cell-cycle after stimulation by a relevant molecular signal.

  • The tumour suppressor genes (that prevent the progression of the cell-cycle)

_There are two families of tumour suppressor genes (or inhibitor genes):

  1. The CDK interacting protein/Kinase inhibitory protein family (or the cip/kip family).

_Members of this family (p21, p27 and p57) halt cell cycle in G1 phase.

_They bind to cyclin-CDK complexes and inactivate them.

_The damaged DNA activates p53 which in turn activate p21 that halts cell cycle in G1 phase.

_The Transforming Growth Factor of β (TGF β) activates p27

  1. The Inhibitor of Kinase 4/Alternative Reading Frame family (or the INK4a/ARF family) that include p14ARF and p16INK4a

_ p14ARF prevents p53 degradation

_ p16INK4a binds to CDK4 and arrests the cell cycle in G1 phase

  • Proto-oncogenes are genes that support cells growth. Occasionally, they mutate or are overproduced leading to uncontrolled multiplication and growth (cancer). The mutated or overproduced proto-oncogenes are known as oncogenes.

_An example of proto-oncogene is  Human epidermal growth factor receptor 2 (HER2/neu) gene that turms into an oncogene when it is overproduced. When this occurs, the cancer is said to be HER2 positive (which can either be breast, colon or any other cancer). HER2 positive cases may not respond well to a typical chemotherapy. However, drugs such as   trastuzumab, have been custom-made to clear cells that are HER2 positive. Before the initiation of chemotherapy, breast cancers are routinely tested for the HER2 status to help in designing of the effective chemotherapy

_Cases of advanced colorectal cancers do not respond to cetuximab and panitumumab if the cancers have mutations in the KRAS gene.

  • The term penetrance indicates the proportion of those carrying a mutation who will have the trait, syndrome, or disease. Complete penetrance occurs when all people who inherit the mutation have the disease while incomplete penetrance refers to cases where not all eople who have the mutation get the disease.
  • The roles of some genes in cancer diagnosis, prognosis monitor and treatment guide:

_The leukemia cells in chronic myeloid leukemia (CML) contain a mutated gene, BCR-ABL. The measurement of this mutation in a sample gives an indication of the prognosis. If the gene is not detected, a conclusion can be made that the cancer cells have been cleared from the body.

_Patients with acute myeloid leukemia (AML) with mutations in the FLT3 gene display poorer prognosis and they require more thorough treatment regime. Contrarywise, people with  NPM1 gene display better prognosis and they require less thorough treatment regime.

_Gene expression panels (transcriptomes) are used in predicting prognosis for a number of cancers e.g. breast, colon, and prostate cancers. Such tests may assist in  predicting the patients whose cancers are likely  re-occur

  1. Nomenclature of tumours and cancers
  • Benign cancers are mostly named as follows: Prefix (of tissue involved) + oma. Malignant cancers are also mainly named as follows: Prefix (of tissue involved) + Sarcoma.
  • Nomenclature of mesenchymal tissues

(Connective tissue, blood or lymphatic tissue)

 

Tissue of origin

Prefix

Benign

Cancer

Malignant cancer

Fat

Lipo-

Lipoma

Liposarcoma

Fibrous

Tissues

Fibr-

Fibroma

Fibrosarcoma

Bone

Osteo-

Osteoma

Osteosarcoma

Cartilage

Chondro-

Chondroma

Chondrosarcoma

Smooth

muscle

Leiomyo

Leiomyoma

Leiomyosarcoma

Striated

Muscle

Rhabdomyo-

Rhabdomyoma

Rhabdomyosarcoma

Blood

vessel

Hemangio-

Hemangioma

Hemangiosarcoma

 

  • Nomenclature of epithelial tissue (glands and linings of surfaces or cavities:

_Malignant cancers have the suffix of  “Carcinoma”

_Finger-like created by tumurs:

*Papilloma when benign

*Papillocarcinoma when malignant

 

Tissue of origin

Prefix

Benign

Cancer

Malignant cancer

Grandular

Aden-

Adenoma

Adenocarcinoma

Symptoms
  • Non-specific symptoms such as fevers, night sweats, persistent pain, cough, fatigue, weight loss and bleeding that manifested as hemoptysis, hematemesis and hematochezia. These symptoms are frequently expressed in occult cancer.
Diagnosis
  • Comprehensive clinical review
  • Biopsy and histopathologic examination - mainly for diagnosis and confirmation.
  • Abnormal laboratory test results (especially when the accompanying interventions are not effective)
  • X-rays and other imaging tests such as ultrasonography, CT, MRI and positron emission tomographypositron emission tomography (PET)
  • Serum tumor markers
Prevention
  • Avoiding;

_obesity

_tobacco

_physical inactivity

_consumption of  inadequate fruits and vegetables

_alcohol

  • Treatment / vaccination against viral infections that are associated with cancers e.g. HBV, HCV and HPV
Management

Cancers are managed as follows;

  • Surgery;

_Removal of tumour  e.g. mastectomy and prostatectomy

_Control of symptoms e.g. spinal cord compression or bowel obstruction (palliative treatment).

_Surgery performed before or after other forms of treatment (known also neoadjuvant)

  • Chemotherapy
  • Radiation therapy
  • Hormonal therapy
  • Targeted therapy (e.g. monoclonal antibody or MAB therapy).
  • Dose-Dense Chemotherapy (DDC);

♦ The tumor growth follows Gompertzian growth curve that represents rapid growth of tumour initially that levels off to slower growth later when it outgrows the available nutrients and blood supply.

♦ It is known that cells are most sensitive to chemotherapy when they are rapidly dividing hence the early stage tumors are generally more sensitive to chemotherapy.

♦ In the standard chemotherapy regimens chemotherapy is administered every 3 or 4 weeks to allow healthy cells to recover between doses. Unfortunately, the 3 or 4- week break allow the smaller and rapidly dividing tumor cells to start growing rapidly again. To reduce this tendency, the DDC reduces dose break interval to 2 weeks.

♦The success of DDC has been attributed partly to the use of growth factors (such as filgrastim and pegfilgrastim) that lead to faster recovery of white blood cells, reducing the chance of infection.

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