What Is Cancer?

• Cancer is an abnormal growth of cells caused by multiple changes in gene expression leading to a dysregulated balance of cell proliferation and cell death and ultimately evolving into a population of cells that can invade tissues and metastasize to distant sites, causing significant morbidity and, if untreated, death of the host.
• Alterations in the expression of multiple genes.
• Dysregulation of the normal cellular program for cell division and cell differentiation.
• Imbalance of cell replication and cell death.
• Favoring growth of a tumor cell population.
• There are a number of mechanisms by which this altered gene expression occurs:
  • A direct insult to DNA, such as a gene mutation, translocation, amplification, deletion, loss of heterozygosity.
  • Mechanism resulting from abnormal gene transcription or translation.
• Malignant neoplasms may resemble normal tissues, at least in the early phases of their growth and development.
• Neoplastic cells can develop in any tissue of the body that contains cells capable of cell division.
• Though they may grow fast or slowly, their growth rate frequently exceeds that of the surrounding normal tissue.
• Diseases in which abnormal cells divide without control and are able to invade other tissues.
• Cancer cells can spread to other parts of the body through the blood and Lymph systems.

Risk Factors of Cancer:

• Smoking: 30% of all cancer cases &90% of lung
• Ionizing radiation.
• Asbestos
• Diet: esp High fat, low fiber &Nitrates.
• Medications : androgens ,estrogens &anthracyclins.
• Infections: EBV, HPV, HCV & HP.
• Chronic inflammation: eg: colon Cancer with Crohn's disease

Why does cancer cause death?

• CNS damage → CNS involvement, E.g:Lymphoma.
• Hemorrhage eg: Gastric Carcinoma.
• Hypercalcemia leading to renal failure .e.g:Breast
• VTE & PE eg: Lung &Colon Cancers.
• Severe weight loss due to vomiting & cancer cachexia g: leukemia.
• Increased risk of fatal cachexia g: Leukemia.
• Obstruction eg: biliary obstruction in pancreatic Cancers.

Medical Terminology

Neoplasia

• It means "new growth" in Greek.
• It is an abnormal proliferation of cells
• The growth of neoplastic cells exceeds and is not coordinated with that of the normal tissues around
• Neoplasia → genetically abnormal cells proliferate in a non­ physiological manner which is unresponsive to normal stimuli (no stimulus).
• Hyperplasia is considered to be a physiological (normal) response to a specific stimulus, and the cells of a hyperplastic growth remain subject to normal regulatory control

Hyperplasia

• It means an increase in the number of cells due to stimulus or injury
• It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia / benign tumor
• Cells may also be increased in size (Hypertrophy).
• Hyperplasia is different from hypertrophy in that the adaptive cell change in hypertrophy is an increase in cell size, whereas hyperplasia involves an increase in the number of cells
• Hyperplasia is considered to be a physiological (normal) response to a specific stimulus, and the cells of a hyperplastic growth remain subject to normal regulatory control
• Stimuli may be:
  • Physiological: mammary gland & genitalia at
  • Hormonal: endometrial hyperplasia due to estrogen

Dysplasia

• from the Greek "malformation'' is a term used in pathology to refer to an abnormality of development.
• This generally consists of an expansion of immature cells, with a corresponding decrease in the number and location of mature cells.
• Dysplasia is characterized by four major pathological microscopic changes:

1. 1. Anisocytosis (cells of unequal size).
   2. Abnormally shaped cells
   3. Hyperchromatism
   4. Presence of mitotic figures (an unusual number of cells that are currently dividing).

Anaplasia

• Refers to a reversion of differentiation in cells and is characteristic of malignant neoplasms.
• Lack of differentiation is considered a hallmark of aggressive malignancies.
• Anaplastic cells are:

1. 1. extremely hyperchromatic (darkly stained) and
   2. The nuclear-cytoplasmic ratio may approach 1:1 instead of the normal 1:4 or 1:6.
   3. Giant cells that are considerably larger than their neighbors may be formed and possess either one enormous nucleus or several nuclei.
   4. Anaplastic forms of tumors are usually highly aggressive:
      1. Anaplastic large cell
      2. Anaplastic T cell

The Classification Of Neoplasms

• Behavioral (Biological)
• Histogenetic

Behavioral (Biological) Classification

Histogenic classification

Malignant neoplasms are divided into categories depending on their embryonic origin:

• Sarcoma: A malignant neoplasm arising from derivatives of the mesodermal (mesenchymal) embryonic germ layer.
• Teratoma: The most common neoplasm of multiple-tissue origin which is derived from all three germ layers.
• Carcinoma: If the neoplasm arises from tissues derived from embryonic ectoderm or endoderm.
• Blastoma: Are types of neoplasms to indicate that the tissue has a primitive appearance that resembles embryonic structures.

The Cytologic Criteria of Cancer

1. The morphology of cancer cells is usually different from and more variable than that of their counterpart normal cells from the same Cancer cells are more variable in size and shape.
2. The nucleus of cancer cells is often larger and the chromatin more apparent ("hyperchromatic") than the nucleus in normal cells; the nuclear-to-cytoplasmic ratio is often higher
3. The number of cells undergoing mitosis is usually greater in a population of cancer cells than in normal tissue. This number, of course, would be higher in normal tissues that have a high growth rate, such as bone marrow.
4. Abnormal mitosis and ''giant cells,'' with large, pleomorphic (variable size and shape) or multiple nuclei, are much more common in malignant tissue than in normal
5. Obvious evidence of invasion of normal tissue by a neoplasm may be seen, indicating that the tumor has already become invasive and may have metastasized

Anatomical Sites of Neoplasms 

The location of the anatomic site of the neoplasm is important for several reasons. The site of the tumor dictates several things about the clinical course of the tumor, including:

• The likelihood and route of metastatic spread.
• The effects of the tumor on body functions.
• The type of treatment that can be employed.
• It is also important to determine whether the observed tumor mass is the primary site (i.e., tissue of origin) of the tumor or a metastasis.
• Primary epidermoid carcinoma of the lung, for example, would be treated differently and have a different prognosis than an embryonal carcinoma of the testis metastatic to the lung.
• It is not always easy to determine the primary site of a neoplasm, particularly if the tumor cells are undifferentiated

The first signs of a metastatic tumor may be a mass in the lung noted on CT scan or a spontaneous fracture of a vertebra that had been invaded by cancer. Because the lungs and bones are frequent sites of metastases for a variety of tumors, the origin of the primary tumor may not be readily evident.

This is a very difficult clinical situation because to cure the patient or to produce long-term remission, the oncologist must be able to find and remove or destroy the primary tumor to prevent its continued growth and metastasis.

Another consideration is the accessibility of a tumor. If a tumor is surgically inaccessible or too close to vital organs to allow complete resection, surgical removal is impossible. For example, a cancer of the common bile duct or head of the pancreas is often inoperable by the time it is diagnosed because these tumors invade and attach themselves to vital structures early, thus preventing curative resection.

Similarly, if administered anticancer drugs cannot easily reach the tumor site, as is the case with tumors growing in the pleural cavity or in the brain, these agents might not be able to penetrate in sufficient quantities to kill the tumor cell

The site of the primary tumor also frequently determines the mode of, and target organs for, metastatic. In addition to the local spread, cancers metastasize via lymphatic channels or blood vessels. For example:

• Carcinomas of the lung most frequently metastasize to regional lymph nodes, pleura, diaphragm, liver, bone, kidneys, adrenals, brain, thyroid, and spleen.
• Carcinomas of the colon metastasize to regional lymph nodes, and by local extension, they ulcerate and obstruct the GIT. The most common site of distant metastasis of colon carcinomas is the liver, via the portal vein, which receives much of the venous return from the colon and flows to the liver.

Some tissues are more common sites of metastasis than others. Because of their abundant blood and lymphatic supply, as well as their function as ''filters'' in the circulatory system, the lungs and the liver are the most common sites of metastasis from tumors occurring in visceral organs.

Metastasis is usually the single most important criterion determining the patient's prognosis. In breast carcinoma, for example, the 5-year survival rate for patients with localized disease and no evidence of axillary lymph node involvement is about 85%; but when more than four axillary nodes are involved, the 5-year survival is about 30%, on average.

Histologic Grade of Malignancy

• The histologic grading of malignancy is based on the degree of differentiation of cancer and on an estimate of the growth rate as indicated by the mitotic index
• It was generally believed that less differentiated tumors were more aggressive and more metastatic than more differentiated tumors. It is now appreciated that this is an oversimplification and, in fact, not a very accurate way to assess the degree of malignancy for certain kinds of tumors.
• However, for certain epithelial tumors, such as carcinomas of the cervix, uterine endometrium, colon, and thyroid, histologic grading is a fairly accurate index of malignancy and prognosis.
• On the basis of this criterion, and others like it, tumors have been classified as:
  • grade I (75% to 100% differentiation),
  • grade II (50% to 75%).
  • grade III (25% to50%).
  • grade IV (0% to 25%).
• More recent methods of malignancy grading also take into consideration mitotic activity, amount of infiltration into surrounding tissue, and amount of stromal tissue in or around the tumor. The chief value of grading is that it provides, for certain cancers, a general guide to prognosis and an indicator of the effectiveness of various therapeutic approaches.

Tumor Staging

• It is a method of discovering the extent of disease on a clinical basis and a universal language to provide standardized criteria among physicians is needed. Attempts to develop an international language for describing the extent of the disease have been carried out by two major agencies:
  • the Union Internationale Contre le Cancer (UICC).
  • American Joint Committee for Cancer Staging and End Results Reporting (AJCCS)
• Some of the objectives of the classification system developed by these groups are:
  • to aid oncologists in planning
  • to provide categories for estimating prognosis and evaluating results of treatment
  • to facilitate the exchange of information.
• Both the UICC and AJCCS schemes use the T, N, M classification system, in which T categories define the primary tumor; N, the involvement of regional lymph nodes; and M, the presence or absence of metastasis. 
• Although the exact criteria used vary with each organ site, the staging categories listed below represent a useful generalization:
  • Stage I (T1 N0 M0): Primary tumor is limited to the organ of origin. There is no evidence of nodal or vascular spread. The tumor can usually be removed by surgical resection. Long-term survival is from 70% to 90%.
  • Stage II (T2 Nl M0): Primary tumor has spread into surrounding tissue and lymph nodes immediately draining the area of the tumor ("first-station" lymph nodes). The tumor is operable, but because of local spread, it may not be completely resectable Survival is 45% to 55%.
  • Stage III (T3 N2 M0): Prima1y tumor is large, with fixation to deeper structures. First-station lymph nodes are involved; they may be more than 3 cm in diameter and fixed to underlying tissues. The tumor is not usually resectable, and part of the tumor mass is left behind. Survival is 15% to 25%.
  • Stage IV (T4 N3 M+): Extensive primary tumor (maybe more than 10 cm in diameter) is present. It has invaded underlying or surrounding tissues. Extensive lymph node involvement has occurred, and there is evidence of distant metastases beyond the tissue of origin of the primary tumor. Survival is under 5%.
• The TNM staging system does not take into account the molecular markers that we now know can more clearly define the status of cancer and as a prognostic indicator, take into account the varied responsiveness of tumors to various therapeutic modalities.
• Thus, treatment choices and prognostic estimates should be based more on the molecular biology of the tumor than the tumor's size, location, or nodal status at the time of diagnosis.                                             

The procedure of work of clinical oncologist

Cancer diagnosis:

• Symptoms: Usually non-specific, Wt loss, Unexplained Chills, Fatigue, an abnormal mass, Haematemesis, Or rectal bleeding.
• Physical examination
• Imaging studies: X-rays, CT, MRI & PET.
• Biopsy & Fine Needle Aspiration
• Tumor Marker Level:  eg: AFP correlates with HCC.

Cancer staging

• Determine the extent of the disease.
• Determine prognosis
• Provide suitable intervention

Cancer therapy

I-Surgery

• Direct tumor removal
• Removal of nearby structures
• Lymph node dissection.

II-Radiation

• Local Modality for treating cancer
• Principle: Act as a catalyst for free radical formation reaction
• Success depends on relative radiosensitivity between normal cells & Cancer Cells
• Delivered as ionizing radiation X-ray or Gamma-ray.
• Has 2 forms:
  • External beam Radiation
  • Brachytherapy: a seed is placed into the tissue where it lets radiation kill cancer cells.
• SE: N, V, Xerostomia, mucositis, BM suppression & 2ry Leukemia

III-Chemotherapy

• Has a greater role in advanced stages of Cancer esp the metastatic forms
• Provide direct cell cytotoxicity.
  • Curative: provide complete remission
  • Palliative: Provide symptoms alleviation.
  • Adjuvant: Chemotherapy after resection of the primary tumor.
  • Neoadjuvant: Chemotherapy used before resection usually with radiation used primarily for downstaging purposes
• Cancer supportive care:
  • Nausea &Vomitting: Provide a prophylactic combination of 5HT₃ antagonist + Dexamethasone.
  • Hypersensitivity reaction: Premedicate with prednisolone + antihistamine
  • Neuropathy: Provide neuronal analgesia.
  • Pain: Provide Opoid analgesics.
  • Haematologic toxicity: Provide CSFs.

IV-Novel

Follow-Up:

• Symptoms severity
• CBC (hematologic malignancy).
• Imaging studies(X-Ray, CT, US, or MRI).
• Tumor markers
• Endoscopy

The terminology used to describe the response to treatment:

1. Complete remission (CR) No clinically detectable cancer is found after
2. Partial remission (PR) Measurable tumor mass decreases  by 50% after treatment, no new areas of tumor development, and no area of tumor shows
3. Minimal remission (MR) is the same as partial remission, but the response does not meet the criteria of 50%
4. Progression The mass (product of diameters) of one or more sites of the tumor increases more than 25%, new lesions appear, or the patient dies as a result of the tumor
5. Stable disease Measurable tumor does not meet the criteria for CR, PR, MR, or Progression.