Neoplasia
Neoplasia means new growth and a new growth formed is known as a neoplasm (Greek, neo = new + plasma = thing formed). They term tumor was originally used for the swelling caused by inflammation, but it is now used synonymously with neoplasm.
Table of Contents
Neoplasia Introduction
Define neoplasia.
Neoplasia means new growth and a new growth formed is known as a neoplasm (Greek, neo = new + plasma = thing formed). They term tumor was originally used for the swelling caused by inflammation, but it is now used synonymously with neoplasm.
Oncology (Greek oncos = tumor) is the study of tumors or neoplasms.
Read And Learn More: Pathology for Dental Students Notes
Willis’s definition: “A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change.”
Salient General Features of Neoplasia:
- Origin: Neoplasms arise from cells that normally maintain a proliferative capacity.
- Genetic disorder: Cancer is due to permanent genetic changes in the cell known as mutations. These mutations may occur in genes that regulate cell growth, apoptosis, or DNA repair.
- Heritable: The genetic alterations are passed down to the daughter tumor cells.
- Monoclonal: All the neoplastic cells within an individual tumor originate from a single cell/or clone of cells that have undergone a genetic change. This tumor is said to be monoclonal.
- Carcinogenic stimulus: The stimulus responsible for uncontrolled cell proliferation may not be identified or is not known.
- Autonomy: In neoplasia, there is the excessive and unregulated proliferation of cells that do not obey normal regulatory control. Their cell proliferation is independent of physiologic growth stimuli. But tumors are dependent on the host for their nutrition and blood supply.
- Irreversible: Neoplasm is irreversible and persists even after the inciting stimulus is withdrawn or gone.
- Differentiation: It refers to the extent to which the tumor cells resemble the cell of origin. A tumor may show varying degrees of differentiation ranging from relatively mature structures that mimic normal tissues (well-differentiated) to cells so primitive that the cell of origin cannot be identified (poorly differentiated)
Classification Of Neoplasia
Discuss the nomenclature and classification of tumors.
Tumors are classified as benign and malignant, depending on the biological behavior of a tumor.
1. Benign tumors: They have relatively innocent microscopic and gross characteristics.
- Remain localized without invasion or metastasis.
- Well-differentiated: Thir cells closely resemble their tissue of origin.
- Prognosis: It is very good, can be cured by surgical removal in most patients and the patient generally survives.
2. Malignant tumors: Cancer is the general term used for malignant tumors. The term cancer is derived from the Latin word for crab, because similar to a crab, malignant tumors adhere to any part that they seize on, in an obstinate manner.
- Invasion: Malignant tumors invade or infiltrate into the adjacent tissues or structures.
- Metastasis: Cancers spread to distant sites (metastasize), where the malignant cells reside, grow, and again invade.
- Exception: Basal cell carcinoma of the skin, which is histologically malignant (i.e. it invades aggressively), but rarely metastasizes to distant sites. Glioma – Malignant tumor of CNS
- Prognosis: Most malignant tumors cause death.
Microscopic Components of Neoplasms:
Tumors (both benign and malignant) consist of two basic components:
- Parenchyma: It is made up of neoplastic cells. The nomenclature and biological behavior of tumors are based primarily on the parenchymal component of the tumor.
- Stroma: It is the supporting, non-neoplastic tissue derived from the host.
Components: Connective tissue, blood vessels, and inflammatory cells (for example, Macrophages, and lymphocytes).
Tumor consistency depends on the amount of stroma:
- Soft and fleshy: These tumors have a scanty stroma.
- Desmoplasia: Parenchymal tumor cells may stimulate the formation of
an abundant collagenous stroma → referred to as desmoplasia. - For example, some carcinoma in the female breast has a stony hard consistency (or scirrhous).
Nomenclature Of Neoplasms
Benign Tumors: A tumor is said to be benign when its gross and microscopic appearances are innocent, remain localized, will not spread to other sites, and can be surgically removed locally, the patient usually survives. They are generally named by attaching the suff “oma” to the cell of origin.
- Mesenchymal Tumors They usually follow the above nomenclature.
- Epithelial Tumors: Their nomenclature is not uniform but more complex.
They are classified in different ways:
1. Cells of origin
2. Microscopic pattern
3. Macroscopic architecture:
- Adenoma: It is a benign epithelial tumor arising from glandular epithelium, although it may or may not form glandular structures.
- Example: Follicular adenoma of the thyroid: It usually shows microscopically numerous tightly packed small glands.
- Papilloma: It is a benign epithelial neoplasm that produces microscopically or macroscopically visible finger-like, exophytic, or warty projections from epithelial surfaces.
- Example: Squamous papilloma.
- Cystadenoma: It is a tumor forming large cystic masses.
- Example: Serous cystadenoma of the ovary.
- Papillary cystadenoma: It is a tumor that consists of papillary structures that project into cystic spaces.
- Example: Papillary serous cystadenoma of ovary.
- Polyp: It is a neoplasm that grossly produces visible projection above a mucosal surface and projects into the lumen. It may be either benign or malignant. It may have a stalk (pedunculated polyp) or maybe without a stalk (sessile polyp).
- Example: Polyp of stomach or intestine.
Malignant Tumors of Neoplasms:
Malignant tumors can invade the adjacent structures spread to distant sites (metastasize) and can cause death. They are termed carcinoma or sarcoma depending on the parenchymal cell of origin.
- Sarcomas: They are malignant tumors arising in mesenchymal tissue. These tumors have little connective tissue stroma and are fleshy (Greek sar = flashy).
- Examples: Fibrosarcoma, liposarcoma, osteosarcoma. Malignant tumors arising from blood-forming cells are called leukemias (literally, white blood) or lymphomas (tumors of lymphocytes or their precursors).
- Carcinomas: They are malignant neoplasms arising from epithelial cells, which may be derived from any of the three germ layers.
- Undifferentiated malignant tumor: It is a malignant tumor composed of undifferentiated cells, where the cell of origin cannot be made out on light microscopic examination.
- Inappropriate terminology for malignant tumor: In certain malignant tumors, the term stuff “oma” is inappropriately used and sounds like a benign tumor.
Nomenclature of Carcinomas:
List Of Malignant Tumors With Suffix Oma:
Mixed Tumors of Neoplasms:
- They are derived from a single germ layer but show divergent differentiation along two lineages.
- Example: A mixed tumor of the salivary gland (pleomorphic adenoma) is derived from a single clone (either myoepithelial or ductal reserve cell) and gives rise to two components, namely epithelial and myoepithelial cells.
Teratomas of Neoplasms:
Write a short note on teratoma.
- They are special types of mixed tumors derived from totipotent germ cells (normally present in the ovary, and testis and sometimes abnormally present in sequestered embryonic rest in midline).
- These cells can differentiate into any of the cell types found in the adult body.
- This teratoma contains recognizable mature or immature cells or tissues representative of more than one germ cell layer and sometimes all three.
- These cells or tissues are arranged in a helter-skelter fashion. The tissues derivative from various germ cell layers may include:
- Ectoderm (for example, Skin, Neural tissue, Glia)
- Mesoderm (for example, Smooth muscle, Cartilage, Bone, fat)
- Endoderm (for example, Respiratory tract epithelium, Gut, Thyroid).
Hamartomas of Neoplasms:
- It is a disorganized mass of benign-appearing cells, indigenous to the particular site.
- Example: Pulmonary chondroid hamartoma consists of islands of disorganized, but histologically normal cartilage, bronchi, and vessels.
Choristoma of Neoplasms:
- It is an ectopic island of normal tissue.
- Heterotopic rest (normal tissue in an abnormal site) is a congenital anomaly.
- Example: Presence of small nodular mass of normally organized pancreatic tissue in the submucosa of the stomach, duodenum, or small intestine.
The nomenclature of the more common forms of neoplasia is listed in Table.
Characteristics Of Benign And Malignant Neoplasms
Describe the characteristics of malignant tumors.
It is very important to differentiate benign from malignant tumors mainly because of the different prognostic outcomes.
In general, benign and malignant tumors can be distinguished on the basis of four fundamental features, namely:
- Differentiation and anaplasia:
- Rate of growth
- Local invasion
1. Differentiation and Anaplasia:
- Differentiation:
- Defined as the extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells. This includes both morphological and functional differentiation.
- Differentiation determines the grade of the tumor.
- Benign Tumors:
- Well-differentiated: The neoplastic cell closely resembles the normal cell of origin.
- It may be not possible to recognize it as a tumor by microscopic examination of individual cells (for example, Lipoma). Only the growth of these cells into discrete lobules discloses the neoplastic nature of the lesion.
- Mitoses: They are rare and of normal configuration.
Malignant Neoplasms:
Write a short note on the histological features of malignant cells.
- Show a wide range of differentiation of parenchymal cells.
- Varies from well-differentiated to completely undifferentiated.
- Cancers are usually graded either as well, moderately or poorly differentiated, or numerically, often by strict criteria, such as grade 1, grade 2, or grade 3.
- Well-differentiated tumors:
- Well-differentiated adenocarcinomas of the colon may form normal-appearing glands.
- Squamous cell carcinomas may show cells that appear similar to normal squamous epithelial cells.
- Poorly differentiated tumors: They consist of cells that have little resemblance to the cell of origin.
- Moderately differentiated: These tumors show differentiation between the well and poorly differentiated tumors.
Anaplasia:
- Anaplasia means “to form backward/backward formation”, i.e. reversal of differentiation of cell to a more primitive level.
- Malignant neoplasms composed of undifferentiated cells are called anaplastic tumors.
- Lack of differentiation (both structural and functional) is called anaplasia and is characteristic of malignancy.
- The degree of anaplasia in a cancer cell correlates with the aggressiveness of the tumor.
- Thus, more anaplastic the tumor becomes more aggressive.
Nomenclature of common tumors:
Microscopic Features of Anaplasia:
Write a short note on anaplasia.
- Pleomorphism:
- It is defined as variation in the size and shape of cells and cell nuclei. It is a feature of malignancy.
- This, cells within the same malignant tumor range from large cells (many times larger than the neighbor cells) to extremely small (primitive appearing) cells.
Write a short note on the morphology of malignant cells.
Abnormal nuclear morphology:
- Extremely hyperchromatic nuclei of tumor cells are due to abundant chromatin and an increased amount of DNA per cell compared to that of a normal cell.
- Microscopically these nuclei stain darkly (hyperchromatic nuclei).
- Nuclear shape and size is variable and may be irregular. Chromatin is coarsely clumped and distributed along the nuclear membrane.
- Large prominent nucleoli are usually seen.
- Mitoses: The presence of mitotic figures indicates the higher proliferative activity of the parenchymal cells
- A number of mitotic: Compared to benign and few well-differentiated malignant tumors, undifferentiated tumors usually show abundant (many) mitotic figures.
- Atypical mitotic figures: Normal mitosis produces bipolar spindles, and one cell divides into two. When the mitotic spindles are more than two, it is called atypical.
- The presence of atypical bizarre mitotic is an important morphologic feature of
malignancy.
- Nuclear cytoplasmic (N: C) ratio: In a normal cell N: C ratio is 1: 4 or 1: 6. In a malignant cell, the nuclei are enlarged, become disproportionately large for the cell, and the nuclear to-cytoplasm ratio may be increased and may reach even up to 1: 1.
- Loss of polarity: The orientation of cells to one another is known as polarity. The anaplastic cells lose the normal polarity → markedly disturbed orientation (architecture) of tumor cells.
- Bizarre cells, including tumor giant cells: Some tumors may show bizarre cells with a single large polymorphic nucleus and others having two or more large, hyperchromatic nuclei.
Functional Changes of Anaplasia:
Well-differentiated tumors usually retain their functional characteristics. The function may be in the form of secretion and vary depending on the tumor type.
- Secretion of normal substances:
- Hormones: Benign tumors and well-differentiated carcinomas of endocrine glands frequently secrete the hormones characteristic of their cell of origin (for example, steroid hormones from an adrenocortical adenoma).
- Normal product: Example: Well-differentiated squamous cell carcinomas produce keratin → form characteristic epithelial pearls.
- Ectopic hormones: Tumors may produce substances that are not indigenous to the tissue of origin. Example: Bronchogenic carcinomas may produce ACTH, parathyroid-like hormone, etc.
2. Rates of Growth:
Factors Determining the Rate of Growth:
- Degree of differentiation
- Benign tumors are well differentiated and usually grow slowly.
- Most malignant tumors grow more rapidly.
- Dependency: Growth also depends on:
- Hormonal stimulation, for example, uterine leiomyomas may suddenly grow during pregnancy and may undergo atrophy after menopause.
- Adequacy of blood supply.
3. Local Invasion:
Benign Tumors:
- Localized: Most benign tumors grow as expansile masses that remain localized to their site of origin.
- No infiltration into adjacent tissue or capsule (if present).
- No metastasis.
- Capsule: It is a rim of compressed connective tissue derived mainly from the extracellular matrix of the surrounding normal tissue.
- Capsule → makes tumor palpable and movable mass → can be surgically enucleated.
- Benign tumors without capsule (unencapsulated). Examples: Hemangiomas, and uterine leiomyoma.
Malignant Tumors of Local Invasion:
- Lack of capsule: Malignant tumors are poorly demarcated from the surrounding normal tissue and lack a true capsule.
- Invasion: The two most reliable features that differentiate malignant from benign tumors are local invasion and metastases.
Local invasion:
- Invasion of adjacent tissue/organ: They cancers may invade and destroy the adjacent tissues/ organ progressive infiltration, invasion, and destruction of the surrounding tissue.
- Tissues that resist invasion: They include mature cartilage (for example, epiphysis), and elastic tissue of arteries.
- Invasion of blood vessels and lymphatics
- Perineural invasion: For example, cancer of the prostate and pancreas, adenoid cystic carcinoma of salivary glands.
Carcinoma In Situ
Some carcinomas evolve from a preinvasive stage called as carcinoma in situ.
Definition of Carcinoma: Carcinoma in situ is defined as:
- A preinvasive epithelial neoplasm.
- Shows all the cytological features of malignancy.
- Involves the entire thickness of the epithelium.
- Remains confined within the epithelial basement membrane.
The tumor cells cannot reach the potential routes of metastasis, such as blood vessels and lymphatics until the basement membrane has been breached or invaded.
Dysplasia
Write a short note on dysplasia.
The cells show cytological features of malignancy and the term dysplasia is used for these changes. It literally means disordered growth. The changes of dysplasia include:
- Cellular pleomorphism.
- Large hyperchromatic nuclei.
- High nuclear-to-cytoplasmic ratio.
- Loss of polarity (architectural orientation).
Classification of Dysplasia:
- Mild
- Moderate
- Severe depending on the thickness of epithelium involved by the dysplastic cells.
Fate of Dysplasia:
- Mild to moderate dysplastic changes, which do not involve the entire thickness of epithelium may be reversible if the cause is removed.
- This dysplasia need not progress to cancer.
- Once the tumor cells breach the basement membrane, the tumor is said to be invasive, and carcinoma in situ may take years to become invasive.
- Most in situ tumors, with time, penetrate the basement membrane and invade the subepithelial stroma.
Sites of Dysplasia: Uterine cervix, skin, and breast.
Asymptomatic: In this stage, tumors are usually asymptomatic.
Metastasis
Define metastasis.
Definition of metastasis: Metastases are tumor deposits that are physically discontinuous with the primary tumor and located in a distant tissue. This process is known as metastasis and the resulting secondary deposits are called metastases.
Significance of metastasis:
Mode of the spread of malignant tumors /Discuss the different modes of metastasis with examples.
- Metastases identify a tumor as malignant because benign neoplasms never metastasize. Exceptions include two malignant tumors, which are locally invasive but rarely metastasize.
- Gliomas (malignant neoplasms of the glial cells) in the central nervous system.
- Basal cell carcinomas of the skin.
- Metastases strongly reduce the possibility of a cure for cancer.
- Metastatic spread is the most common cause of cancer death.
Factors favoring metastasis:
- Poorly differentiated tumor
- A more rapidly growing tumor
- Large primary tumor.
Morphological Appearance of metastasis:
- Microscopically, metastases resemble the primary tumor. But occasionally, they may be so anaplastic that their cell of origin cannot be made out.
- Unknown primary: Sometimes metastases may appear without any clinically detectable primary tumor.
Pathways Of Spread
The invasiveness of cancers allows them to penetrate blood vessels, lymphatics, and body cavities.
It provides an opportunity for the spread/dissemination of cancers through the following pathways:
1. Lymphatic Spread:
Write a short note on the lymphatic spread of malignant tumors.
- The most common pathway of spread for carcinomas.
- Regional node involvement: Once the tumor cells gain access to the lymphatic vessels, they are carried to the regional draining lymph nodes.
- The pattern of lymph node involvement follows the natural routes of lymphatic drainage.
- A sentinel lymph node biopsy is done to know the presence or absence of metastatic lesions.
- Skip metastasis: When local lymph nodes are bypassed and lymphatic metastases develop in lymph nodes distant from the site of the primary tumor; these are called “skip metastasis”.
- Example: Abdominal cancers may be first detected by an enlarged supraclavicular node.
The microscopic pattern of deposits:
- Initially, tumor cells are deposited in the marginal sinus and later extend throughout the node.
- Micrometastases consist of single tumor cells or very small clusters.
Significance of lymph node metastases:
Prognostic value, for example, in breast cancer, involvement of axillary lymph nodes is very important for assessing prognosis and for the type of therapy.
2. Hematogenous Spread:
Write a short note on the hematogenous spread of malignant tumors.
Hematogenous spread is usual for sarcomas but is also found in carcinomas. Blood-borne metastasis usually occurs in osteosarcoma, choriocarcinoma, and renal cell carcinoma.
- Vessels invaded: Cancer cells easily invade capillaries and venules but thick-walled
arterioles and arteries are relatively resistant. - Tumors with an affinity for venous invasion:
- Renal cell carcinoma: It can invade the renal vein and grow in a snakelike fashion up the inferior vena cava, sometimes reaching the right side of the heart.
- Hepatocellular carcinoma: It may invade branches of the portal and hepatic vein and grow within the main venous channels.
- The pattern of involvement: With the venous invasion, the pattern of metastases follows the venous flow.
The target organ for metastasis:
- Liver and lungs: They are the most frequently involved organs because all portal area drains to the liver. Tumors that penetrate systemic veins, eventually drain into the vena cava. Since all caval blood flows to the lungs, it is the other common site for secondaries by hematogenous spread.
- Bone metastasis: Cancer metastasizes to bone-prostate, lung, breast, liver, intestine, kidney, and thyroid.
- The vertebral column is the common site and spreads through the paravertebral plexus.
- Example: Carcinomas of the thyroid and prostate.
- Other common sites: The brain’s most common primary is lung cancer, kidney, and adrenals.
- Organs are relatively resistant: For example, skeletal muscle and spleen.
Morphology of Spread:
- Gross appearance: Appear as multiple round nodules of varying sizes found throughout the organ.
- Microscopy: The metastatic deposits generally resemble the structure of the primary tumor.
3. Seeding of Body Cavities and Surfaces:
1. Transcelomic spread:
- Malignant tumors arising in organs adjacent to body cavities (for example, ovaries, gastrointestinal tract, and lung), may seed body cavities. The malignant cells may exfoliate or shed from the organ surfaces into the body cavities and cytological examination of this fluid may show malignant cells.
- Such body cavities include peritoneal (most common), pleural cavities (common), pericardial (occasionally), joint space, and subarachnoid space.
- Peritoneal cavity:
- Example: Ovarian tumors, such as primary carcinomas of surface epithelial origin and Malignant GI tract tumors may spread to involve the peritoneal cavity → ascites.
- Pleural cavity: Peripherally situated lung tumors → pleural effusions.
- Cerebrospinal fluid: Glioblastoma commonly spreads through CSF in the subarachnoid space to the spinal cord.
- Peritoneal cavity:
2. Spread along the epithelial lined spaces: It is not common. Examples:
- Carcinoma endometrium may spread to the ovary (or vice versa) through the fallopian tube.
- Carcinoma of the kidney may spread to the lower urinary tract via ureters.
4. Direct Transplantation
- Tumor cells may be directly transplanted (for example, by surgical instruments like scalpel, needles, sutures) or implantation by direct contact (for example, transfer of cancer of lower lip to the corresponding opposite site in the upper lip).
- Even though this method is theoretically possible, they are rare.
- Differences between benign and malignant tumors are summarized in Table.
Precancerous Conditions/Lesions
Write a short note on precancerous lesions/premalignant neoplasms.
Precancerous conditions are non-neoplastic disorders in which there is a well-defined association with an increased risk of cancer. However, in majority of these lesions, no malignant neoplasm develops except that they have an increased risk. Examples:
- Chronic atrophic gastritis of pernicious anemia.
- Solar keratosis of the skin.
- Chronic ulcerative colitis. It results from the accumulation of complementary mutations in a stepwise fashion over time.
- Leukoplakia (erythroplakia) of the oral cavity, vulva, and penis.
- Barrett’s esophagus.
- Squamous metaplasia and dysplasia of bronchial mucosa were observed in chronic smokers.
- Endometrial hyperplasia and dysplasia in women with unopposed estrogen stimulation.
- Precancerous benign tumors: A few forms of benign tumors may transform into malignant ones.
- Example: Villous adenoma of the colon, as it increases in size, becomes malignant.
- Benign develops occasionally into malignant: Most benign tumors do not become malignant. However, occasionally it may arise from benign tumors. Examples:
- Leiomyosarcoma begins in a leiomyoma.
- Carcinoma developing in long-standing pleomorphic adenomas.
- Malignant peripheral nerve sheath tumor in patients with neurofibromatosis.
- Congenital abnormalities may predispose to cancer.
- Example: The undescended testis is more prone to neoplasms than the normally located testis.
Discuss the differences between benign and malignant tumors.
Differences between benign and malignant tumors:
Molecular Basis Of Cancer
Fundamental Principles:
- Cancer is a genetic disease that arises through a series of somatic alterations in DNA that result in uncontrolled proliferation.
- Nonlethal genetic damage (mostly in DNA) known as mutations is essential for carcinogenesis because lethal damage cause the death of cells. The mutation may be:
- Inherited in the germ line and occurs in certain families.
- Acquired by the action of environmental agents (for example, chemicals, viruses, or radiation) and result in sporadic cancers.
- Tumors are monoclonal, i.e. they originate from a clonal proliferation of a single type of progenitor cell that has undergone genetic damage.
- Carcinogenesis is a multistep process.
Four classes of normal regulatory genes are the main targets of genetic damage.
1. Growth-promoting proto-oncogenes:
- The mutation of normal cellular genes known as proto-oncogenes produces genes that lead to tumor formation and are known as oncogenes.
- They behave as dominant genes.
2. Growth-inhibiting tumor suppressor genes:
- They normally prevent uncontrolled growth.
- Usually, both normal alleles of the tumor suppressor genes must be damaged/ mutated before the transformation of cell can occur.
Two groups of tumor suppressor genes are:
1. Governors and
2. Guardians.
- Governor gene mutations → remove the brake for cellular proliferation → neoplasia, for example, RB gene.
- Guardian genes since the genomic damage and prevent the proliferation of cells with genetic damage or if the damage is too severe to be repaired → induces apoptosis, for example, p53.
3. Genes involved in DNA repair: Normally, they repair nonlethal damage in other genes, including proto-oncogenes, tumor suppressor genes, and genes that regulate apoptosis.
- Mutations of DNA repair genes do not directly transform cells.
- Disability in the DNA-repair genes can predispose cells to widespread mutations in the genome → neoplastic transformation.
4. Genes that regulate programmed cell death (apoptosis): They can behave as protooncogenes (loss of one copy is enough) or tumor suppressor genes (loss of both copies required).
Steps In Normal Cell Proliferation
Normal cell follows a controlled proliferation. The different sequential steps are:
- Growth factors are binding to its specific cell surface receptor.
- Transient and limited activation of the growth factor receptor → activates signal-transuding proteins on the inner aspect of the cell membrane. Following this signaling, the receptor reverts to its resting state.
- Intracellular signal transduction:
- Most of the signal-transducing proteins are located on the inner aspect of the plasma membrane.
- They receive external signals get activated (by binding of growth factor to its growth factor receptors) and transmit the growth signal across the cytoplasm → to the nucleus of the cell. The most important signal-transducing protein belongs to the RAS family and ABL.
- Transcription: Activation of nuclear regulatory factors → initiates DNA transcription.
- Cell cycle: Entry and progression of the cell into the cell cycle → resulting in cell division.
Hallmarks Of Cancer
Normal cells may undergo malignant transformation by corrupting any one of the normal steps involved in cell proliferation. All cancers show eight fundamental changes in cell physiology.
These are considered the hallmarks of cancer and include:
- Self-sufficiency in growth signals.
- Insensitivity to growth-inhibitory signals.
- Altered cellular metabolism.
- Evasion of cell death/apoptosis.
- Limitless replicative potential.
- Development of sustained angiogenesis.
- Ability to invade and metastasize.
- Ability to evade the host immune response.
1. Self-sufficiency in Growth Signals: Oncogenes
Write a short note on the oncogene.
Proto-oncogenes are normal cellular genes, which encode several nuclear proteins that regulate normal cell proliferation, differentiation, and survival.
Oncogenes and Oncoproteins: Genes that promote autonomous cell growth in cancer cells are called oncogenes and are altered/mutated versions of proto-oncogenes.
- Oncogenes can promote cell growth in the absence of normal growth-promoting/mitogenic signals.
- Products of oncogenes → are called oncoproteins, which resemble the normal products of proto-oncogenes.
- Oncoprotein production is not under normal regulatory control → Cells proliferate without the usual requirement for external signals and are freed from checkpoints → growth becomes autonomous.
Classification of oncogenes: Oncogenes can be classified according to the function of the gene product (oncoprotein).
- Growth factors (for example, SIS coding for platelet-derived growth factor)
- Growth factors receptors (for example, ERBB coding for epidermal growth factor receptor)
- Signal transduction proteins (for example, RAS and GTP)
- Nuclear-regulatory proteins (for example, MYC)
- Cell cycle regulators (for example, Cyclins).
2. Insensitivity to Growth-Inhibitory Signals (Tumor Suppressor Genes):
- Normally, the products of tumor suppressor genes have a negative regulatory control of cell growth.
- So, a second mechanism of carcinogenesis results from failure of growth inhibition, due to deficiency of normal tumor suppressor genes and their products.
General Characteristic Features of Tumor Suppressor Genes:
Define cancer suppressor genes.
- Apply brakes to cell proliferation: Oncoproteins stimulate cell proliferation; whereas the products of tumor suppressor genes apply brakes and prevent uncontrolled cell proliferation.
- Two important tumor suppressor genes are
- RB and
- TP53 gene.
- Mutations of tumor suppressor genes may be hereditary and spontaneous.
1. Retinoblastoma Gene (RB gene):
- RB (RB1) gene was the first discovered tumor suppressor gene, which is present on chromosome locus 13q14.
- Inactivation of the RB gene was found in retinoblastoma, which is a rare malignant childhood tumor derived from the retina.
- Retinoblastoma may occur either as a hereditary or sporadic form.
Method of inactivation of RB gene and associated tumors:
- Mutations/loss of RB gene: It may be:
- Germline mutation, for example, In retinoblastomas and osteosarcomas.
- Acquired mutation, for example, In glioblastomas, small-cell carcinomas of the lung, breast
cancers, and bladder carcinomas.
- Blocking of RB function: It may occur even without RB mutation.
- Example: E7 protein of Human Papilloma Virus (HPV) binds to the hypophosphorylated RB → prevents binding of RB protein with E2F transcription factors → free E2F causes progression of cell cycle → cervical carcinomas.
2. TP53 Gene:
TP53 is a tumor suppressor gene located on the small arm of chromosome 17(17p13). Its protein product p53 is present in almost all normal tissues. TP53 is one of the most commonly mutated gene in cancer.
Functions of p53:
- Guardian of the genome: It functions as a critical gatekeeper gene. It plays a main role in maintaining the integrity of the genome and This is known as the guardian of the genome or “molecular policeman.”
- The normal role of p53: When there is DNA damage, telomere shortening or other stresses (for example, hypoxia) → activates p53 → increases p53 levels → leads to arrest of the cell cycle at G1 phase.
- p53 also induces the DNA repair gene: Cell cycle arrest gives time for the cells to repair DNA damage. During this time the damaged DNA may be either repaired or damage may persist.
- Prevention of neoplastic transformation: p53 prevents the neoplastic transformation of cells by three interconnected mechanisms:
- Activation of temporary cell cycle arrest (quiescence)
- Activation of permanent cell cycle arrest (senescence)
- Triggering programmed death of cells with damaged DNA (apoptosis).
Method of inactivation of the p53 gene and associated tumors: Most cancers have defects in the p53 gene.
- Mutations or deletion of the TP53 gene: It allows cells with damaged DNA to progress through the cell cycle → neoplastic transformation.
- Blocking of p53 function: Similar to RB, the function of the p53 may be blocked even without mutation in p53. Example: Similar to RB, some DNA tumor viral products like HPV E6, promote p53 degradation.
3. Growth-Promoting Metabolic Alterations: The Warburg Effect:
- Cancer cells show a distinctive form of cellular metabolic alteration (even in the presence of adequate oxygen) characterized by high levels of glucose uptake and increased conversion of glucose to lactose (fermentation) via the glycolytic pathway.
- This is known as the Warburg effect or aerobic glycolysis.
- Warburg effct provides rapidly dividing tumor cells with metabolic intermediates that are needed for the synthesis of cellular components.
- This helps in the promotion of tumor growth.
4. Evasion of Apoptosis:
- Apoptosis is a programmed cell death and is one of the normal protective mechanism by which a cell with DNA damage (mutation) undergo cell death.
- Mutations in the genes that regulate apoptosis may result in the accumulation of neoplastic cells.
Methods of Evasion of Apoptosis and Associated Tumors:
Tumor cells may escape or undergo reduced apoptosis. Reduced apoptosis may be due to the activation of either antiapoptotic proteins or reduced proapoptotic activity.
- Activation of antiapoptotic Bcl-2: For example, Follicular lymphomas (about 85%) show a characteristic chromosomal translocation, t(14;18), causing overexpression of The antiapoptotic Bcl-2 protein. Neoplastic B lymphocytes are protected from undergoing apoptosis and survive for long periods.
- Reduced levels of proapoptotic BAX: The p53 induces apoptosis of cells that are unable to repair DNA damage partly by transcriptional activation of proapoptotic BAX. Mutation of p53 leads to reduced levels of BAX resulting in decreased apoptosis.
5. Limitless Replicative Potential: Telomerase
All malignant tumors contain cells that are immortal and have limitless replicative potential.
- Cancer Stem Cells: A least few cells in all cancers have stem cell-like properties and are called cancer stem cells. They may be formed either through the transformation of a normal stem cell or through acquired genetic lesions that produce a stem-like state on a more mature cell.
- Reactivation of telomerase:
- Most normal cells can undergo cell division about 60 to 70 times.
- Telomere is the special structure present at the ends of chromosomes. During each cell division, a small section of the telomere is not duplicated resulting in progressive shortening, which is responsible for the limited replicative property of a cell.
- During repeated cell cycles, there is progressive shortening of telomeres, which is prevented by an enzyme called telomerase.
- Telomere maintenance is seen in many types of cancers.
- Cancer cells acquire lesions that inactivate senescence signals and reactivate telomerase, which act together to convey limitless replicative potential.
6. Development of Sustained Angiogenesis:
- Vascularization of tumor: Solid tumors cannot grow without vascularization and is achieved mainly by neoangiogenesis (common) in which new vessels sprout from existing capillaries.
- Angiogenesis is controlled by a balance between angiogenic promoters and inhibitors that are produced by tumor and stromal cells.
- In tumors, this balance is tilted in
favor of promoters.
Effects of neovascularization:
- Supplies nutrients and oxygen.
- Secretion of growth factors by newly formed endothelial cells, which stimulate the
growth of adjacent t - Favor metastasis.
7. Invasion–Metastatic Cascade (Molecular Events in Invasion and Metastasis)
Discuss the mechanism of invasion and metastasis.
Invasion and metastasis are characteristic of malignant tumors.
Definition of invasion and metastasis: Invasion–metastatic cascade constitutes the entire sequence of events from the beginning of invasion to the development of metastasis.
Phases of invasion and metastasis:
- Invasion–metastatic cascade is a complex multistep process. It can be divided into two main phases namely:
- Invasion of the extracellular matrix (ECM) and
- Metastasis (vascular dissemination and homing of tumor cells).
Invasion of Extracellular Matrix:
Tumor cells must interact with ECM (including basement membrane and interstitial tissue) at several steps in the invasion–metastatic cascade.
Invasion of the ECM is an active process and consists of 4 steps:
1. Loosening of tumor cells: Normal cells are attached by adhesion molecules namely E-cadherins.
- Reduced/loss of E-cadherin function: It is observed in most epithelial cancers (for example, adenocarcinomas of the colon and breast) → loosening of tumor cells. The separated cells get detached from the primary cancer.
2. Local degradation/proteolysis of basement membrane and interstitial connective tissue:
The extracellular matrix is of two types namely:
- Basement membrane and
- Interstitial connective tissue.
Secretion of degrading enzymes:
- Malignant tumor cells and stromal cells (for example, fibroblasts and inflammatory cells) in cancers secrete/induce many proteolytic enzymes that degrade ECM.
- These enzymes include: Matrix metalloproteinases (MMPs), cathepsin, and urokinase plasminogen activator (u-PA).
- Local degradation of basement membrane and interstitial connective tissue: This is achieved by proteolytic enzymes.
3. Changes in attachment/adhesion of tumor cells to ECM proteins: Normal epithelial cells have receptors (for example, Integrin) for basement membrane components (for example, laminin and collagen) and are located at their basal surface.
- Generation of new sites: Local degradation of the basement membrane generates new and strange sites in the basement membrane.
- Adhesion of tumor cells to ECM: The receptors on tumor cells attach to the new sites in the basement membrane.
- Stimulation of tumor cell migration: It follows the attachment/adhesion of tumor cells to ECM proteins.
4. Locomotion/migration of tumor cells through degraded ECM: It is a multi-step process.
- Locomotion/migration drives the tumor cells forward through the degraded basement membranes and zones of proteolysis in the interstitial connective tissue matrix.
- Locomotion involves many receptors and signaling proteins.
- The locomotion is potentiated by tumor cell-derived cytokines, such as autocrine motility factors (AMF) and other molecules.
- Migration through interstitial tissue: The tumor cells invade and traverse through
the surrounding interstitial connective tissue and ultimately reach nearby blood and lymphatic vessels. Cells gain access to circulation by penetrating the basement membrane of vessels.
Metastasis (Vascular Dissemination and Homing of Tumor Cells):
Following the invasion of surrounding interstitial tissue, malignant cells may spread to distant sites by metastasis. Metastasis is the multistep process by which a tumor produces a secondary growth at a distant site or location.
It has several steps:
- Penetration of vascular or lymphatic channels (intravasation into the lumen of vessels): Malignant cells penetrate the basement membrane of blood vessels or lymphatic channels.
- Invasion of the circulation and formation of tumor emboli: Tumor cells that have entered the circulation may be either destroyed by host immune cells or survives. Survived tumor cells may aggregate to form tumor emboli.
- Transit through the circulation.
- Arrest within circulating blood or lymph: It occurs at a distant location away from the primary tumor. At the site of arrest tumor cells adhere to endothelial cells.
- Exit from the circulation into a new tissue site: Occurs through the basement membrane of lymphatics or blood vessels. The site at which circulating tumor cells leave the vessel or lymphatics must repeat the same events involved in the invasion but in reverse order.
- Formation of micrometastases: Tumor cells lodge at a distant new site to form micrometastases. Examples of favored sites of metastasis:
- Prostatic carcinoma to the bone.
- Bronchogenic carcinomas to the adrenals and to the brain.
- Neuroblastomas to the liver and bones.
- Angiogenesis.
- Local growth of micrometastases into the macroscopic tumor.
8. Evasion of Immune Surveillance (Host Defense):
- The immune system can identify the tumor cells as non-self and destroy those cells.
- Antitumor activity is mainly mediated by cell-mediated mechanisms.
- Different classes of tumor antigens include products of mutated proto-oncogenes, tumor suppressor genes, overexpressed or aberrantly expressed proteins, tumor antigens produced by oncogenic viruses, etc.
- Immunosuppressed patients have an increased risk for the development of cancer, especially those produced by oncogenic DNA viruses.
- In immunocompetent patients, tumors may avoid the immune system by several mechanisms.
Genomic Instability as Enabler of Malignancy:
- The third class of genes in which mutations contribute to the pathogenesis of cancer are DNA repair genes. DNA repair genes protect the integrity of the genome.
- Individuals with inherited defects in DNA repair genes are at increased risk of developing cancer.
- DNA-repair genes are not oncogenic by themselves, but their defect allows mutations in other genes to progress during cell proliferation.
- Usually, genomic instability develops when both copies of the DNA repair genes are lost. Different types of DNA repair genes defects and associated conditions are shown.
Etiology Of Cancer (Carcinogenic Agents)
Classify carcinogens /enumerate the types of carcinogens.
Definition of carcinogens:
A carcinogen is an agent known or suspected to cause tumors and such agents are said to be carcinogenic (cancer-causing).
Carcinogenic agents :
- Chemicals
- Microbial agents, and
- Radiation.
1. Chemical Carcinogenesis
List major chemical carcinogens and describe in detail chemical carcinogenesis.
- Sir Percival Pott (London surgeon) first related scrotum skin cancer in chimney sweeps to specific chronic chemical exposure to soot. Based on this, a rule was made that chimney sweep members must bathe daily, and this public health measure controlled scrotal skin cancer.
- Japanese investigators (Yamagiva and Ichikawa) experimentally produced skin cancers in rabbits by using coal tar. Subsequently, hundreds of chemical carcinogens were discovered.
Classification of Chemical Carcinogens:
Chemical carcinogens may be classified into two categories: Direct acting and indirect acting. Major chemical carcinogens are listed in Table.
1. Direct-acting Agents:
Direct-acting chemical agents do not require metabolic conversion to become carcinogenic, but most of them are weak carcinogens. Some of the drugs (for example, Alkylating agents) used to cure, control, or delay the recurrence of some cancers (for example, leukemia, lymphoma), may produce a second form of cancer (for example, acute myeloid leukemia) later.
Alkylating agents:
- Source: Many cancer chemotherapeutic drugs (for example, Cyclophosphamide, cisplatin, busulfan) are alkylating agents.
- Mechanism of action: Alkylating agents contain electron-deficient atoms that react with electron-rich atoms in DNA. These drugs not only destroy cancer
- Cancers produced: Solid and hematological malignancies.
Major chemical carcinogens:
2. Indirect-acting Agents (Procarcinogens):
Write a short note on polycyclic hydrocarbons.
These chemicals require metabolic activation for conversion to an active ultimate carcinogen.
Polycyclic aromatic hydrocarbons: They are the most potent and extensively studied indirect-acting chemical carcinogens.
Examples: Benzo(a)pyrene, 3-methylcholanthrene, and Dibenzanthracene.
Source:
- Originally derived from coal tar and fossil fuels.
- Cigarette smoke: Polycyclic aromatic hydrocarbons are formed during high-temperature combustion of tobacco in cigarette smoking → responsible for lung cancer in cigarette smokers.
- Animal fats: These may be produced it during the process of broiling meats.
- Smoked food: Examples, are smoked meats and fish.
Mechanism of action:
- Polycyclic hydrocarbons are metabolized by cytochrome P450-dependent mixed
function oxidases to electrophilic (have electron-deficient atoms) epoxides. - Epoxides react with proteins and nucleic acids (DNA, RNA). Example: Polyvinyl chloride (used in the plastic industry) is metabolized to an epoxide → causing hepatic angiosarcomas.
- Cancers produced: The specific type of cancer produced depends on the route of
administration. - Examples: Cancers in the skin, soft tissues, lungs, and breasts.
Aromatic amines and azo dyes:
They are indirect-acting carcinogens.
Source:
- In the past, aromatic amines (β-naphthylamine) and azo dyes were used in the aniline dye and rubber industries.
- Azo dyes were used for coloring food (for example, Butter and margarine, which give yellow color, scarlet red for coloring cherries).
Mechanism of action:
- They are not carcinogenic at the point of application.
- Both aromatic amines and azo dyes are mainly metabolized in the liver.
- The aromatic amines are converted to active carcinogenic in the liver. However, can be detoxified immediately by conjugation with glucuronic acid in the liver.
- The conjugated metabolite is excreted in the urine and deconjugated in the urinary
tract by the enzyme glucuronidase. - The urothelium is exposed to the active carcinogen (reactive hydroxylamine) which may cause bladder cancer. (azo dyes).
3. Natural microbial product:
Aflatoxin B 1:
- Source: Aflatoxin B1 is a natural product of Aspergillus favus, a mold that grows on improperly stored grains and peanuts.
- Mechanism of action: Metabolized to an epoxide binds to DNA and also produces mutations of the p53 gene.
- Cancers produced: Powerful liver carcinogen → hepatocellular carcinoma.
4. Others:
Nitrosamines: They are potent carcinogens.
- Source: Before the advent of refrigerators, nitrites were added as a preservative for meats and other foods.
- Mechanism of action: Nitrites react with amines and amides in the diet and are metabolized by commensal bacteria within the gut and converted to carcinogenic nitrosamines.
- Cancers produced: Mainly gastrointestinal neoplasms.
- Metals: Compounds like arsenic, nickel, lead, cadmium, cobalt, chromium, and beryllium can produce cancer. Most metal-induced cancers occur due to occupational exposure.
- Asbestos: Inhalation of asbestos fibers → results in asbestosis, pleural plaques, mesothelioma, and carcinoma of the lung. Mesothelioma may involve the pleura as well as the peritoneum.
Mechanism of Action of Chemical Carcinogens:
Molecular targets of chemical carcinogens: Most chemical carcinogens are mutagenic. A mutagen is an agent, which can permanently alter the genetic constitution of a cell.
- All direct and ultimate carcinogens (of indirect carcinogens) contain highly reactive electrophilic groups → form adducts with DNA, RNA, and proteins.
- Genes affected: Any gene may be affected but commonly involved are proto-oncogenes (RAS) and tumor suppressor genes (p53).
Multistep Hypothesis:
- Chemical carcinogenesis is a multistep process. Once the tumor process is started, it does not require the continued presence of the carcinogen.
- Four steps involved in chemical carcinogenesis are:
1. Initiation: It is the first important step that develops from exposure of cells to a sufficient dose of a carcinogenic agent (initiator).
- Reaction with DNA: All initiators are highly reactive electrophiles (electron-deficient atoms) and can react with nucleophilic (electron-rich) sites in the cell. Sites of reaction of initiation are DNA, RNA, and proteins.
- Effect of initiation: Initiators produce nonlethal permanent (irreversible) alterations or damage to DNA (mutations) in a cell. If damage is lethal or severe it causes cell death.
2. Promotion: Promoters in carcinogenesis.
Differences between initiators and promoters:
- Promoters: They are noncarcinogenic agents and cannot directly damage DNA (mutation).
- Cell proliferation: Promoters stimulate the initiated (with permanent DNA damage mutated) cells to enter into the cell cycle → cell proliferation. Unlike initiators, the cellular changes produced by promoters are reversible.
- Produce changes only on initiated cell: Tumors develop only if the promoter is applied after the initiator and not the reverse way.
- Examples of promoters include phorbol esters, hormones, phenols, and drugs.
- Progression: Continuous proliferation of initiated cells → leads to secondary genetic abnormalities → Tumor growth becomes independent of the initiator or the promoter (i.e. autonomous). Many accumulated mutations finally immortalize the cells.
4. Cancer: The final result of the different steps is the development of neoplasm → invasion → metastases.
Examples: The morphologic sequence of hyperplasia, dysplasia, and carcinoma in situ found in the epithelium (for example, Skin, cervix, and colon) indicate multistep carcinogenesis.
Microbial Carcinogenesis:
Viruses that cause tumors are called oncogenic viruses. Many viruses have been proven to be oncogenic in animals, but only a few have been associated with human cancer.
Classify/List oncogenic viruses.
Classification: They are mainly classified depending on the genetic material into:
- Oncogenic RNA viruses and
- Oncogenic DNA viruses.
1. Oncogenic RNA Viruses:
- Human T-cell leukemia virus type 1: It is a retrovirus.
- A major target for neoplastic transformation: CD4+ T lymphocytes.
- The tumor caused by adult T-cell leukemia/lymphoma—develops after a long latent period (20 to 50 years).
- Mode of infection:
- Sexual intercourse
- Blood products, and
- Breastfeeding.
2. Oncogenic DNA Viruses:
Five DNA viruses can cause cancer. HCV is not a DNA virus and found to be associated with cancer.
Human Papilloma Virus (HPV):
Write a short note on oncogenesis by human papillomavirus.
- A cell infected: Human papillomaviruses (HPV) infect only the immature squamous cells but its replication occurs in the maturing, nonproliferating squamous cells.
- This, their full productive life cycle occurs only in squamous cells. The physical state of the virus differs in different lesions.
- Types of HPV and associated lesions: More than 70 genetically different types of HPV have been identified. They are divided into low-risk and high-risk HPVs.
Mode of Action:
Episomal form: In benign lesions such as benign warts, condylomata, and most precancerous lesions; the HPV genome is present as nonintegrated, free (episomal) viral DNA.
Integration: In cancers, the HPV genome is integrated into the host genome and is essential for malignant transformation. Integration results in the overexpression of the two viral genes E6 and E7. Protein products of E6 and E7 (oncoproteins) are important for the oncogenic Effects of HPV.
Actions of E7 protein:
- Inactivation of tumor suppressor RB gene: E7 protein binds to the hypophosphorylated (active) form of RB protein → releases its inhibitory effect on cell cycle progression.
- Inactivation of inhibitors of the cell cycle: For example, inactivation of CDKIs (CDKN1A/ p21 and CDNK1B/p27) → activates the cell cycle.
- Activation of cyclins (activators of the cell cycle): These include cyclins E and A → facilitates G2/M transition → activation of the cell cycle.
Actions of E6 protein: The E6 protein complements the Effects of E7.
- Inactivation of tumor suppressor p53 gene: E6 binds and degrades p53 → degrades BAX (a proapoptotic factor) → prevents apoptosis.
- Activation of telomerase: E6 up-regulates telomerase → prevents replicative senescence and cell proliferation continues.
The combined action of E6 and E7: They induce centrosome duplication and genomic instability.
2. Epstein-Barr Virus (EBV):
EBV is a human herpesvirus, which infects B lymphocytes. Patients may manifest as short-lived infectious mononucleosis or develop a few human cancers. The list of cancers produced includes:
- African form of Burkitt lymphoma.
- B-cell lymphomas in immunosuppressed (for example, HIV infection or immunosuppressive therapy after organ transplantation).
- A subset of Hodgkin lymphoma.
- Nasopharyngeal carcinoma (T cell tumor).
- Some gastric carcinomas.
- Rare forms of T cell lymphomas and natural killer (NK) cell lymphomas.
- Very rarely sarcomas.
3. Hepatitis B and C Viruses:
HBV is a DNA virus whereas HCV is an RNA virus. There is a strong association between chronic infection with HBV and HCV (chronic hepatitis and cirrhosis) with primary hepatocellular carcinoma.
4. Human Herpesvirus 8 (HHV 8):
It is a DNA virus, which infects the spindle cells of Kaposi sarcoma and is also lymphocytes.
Neoplasm produced:
- Kaposi sarcoma: It is a vascular neoplasm, which is the most common neoplasm, associated with AIDS. HHV 8 has also been found in Kaposi sarcoma from HIV-negative patients.
- B-cell lymphoid malignancies: Two uncommon lymphoid malignancies, namely, primary effusion lymphoma and multicentric Castleman disease are associated with
Various viruses implicated in human tumors and associated lesions:
Bacteria:
- Helicobacter pylori
- Diseases caused by H. pylori are:
- Peptic ulcers
- Gastric adenocarcinomas, and
- Gastric lymphomas.
- Gastric lymphoma: H. pylori produces lymphoma of B-cell origin and are called lymphomas of mucosa-associated lymphoid tissue, or MALTomas.
Radiation Carcinogenesis:
Radiation is a well-known carcinogen.
Latency of radiation:
- The extremely long latent period is common and it has a cumulative effect.
- Radiation has also additive or synergistic Effects with other potential carcinogenic agents.
Types of radiation: They are divided into two types, namely:
- Ultraviolet (UV) rays of sunlight, and
- Ionizing electromagnetic and particulate radiation.
1. Ultraviolet Rays:
They are derived from sunlight.
Tumors caused: Skin cancer namely:
- Squamous cell carcinoma
- Basal cell carcinoma
- Malignant melanoma.
They are more common on parts of the body regularly exposed to sunlight, and ultraviolet light (UVL).
Risk Factors of Ultraviolet Rays:
The amount of damage incurred depends on:
- Type of UV rays
- Intensity of exposure
- The protective mantle of melanin:
- Melanin absorbs UV radiation and has a protective effect.
- Skin cancers are more common in fair-skinned people and those living in geographic locations receiving a greater amount of sunlight (for example, Queensland, Australia, close to the equator).
Pathogenesis of Ultraviolet Rays:
- UV radiation leads to → formation of pyrimidine dimers in DNA, which is a type of DNA damage that is responsible for carcinogenicity.
- DNA damage is repaired by the nucleotide excision repair pathway.
- With excessive sun exposure, the DNA damage exceeds the capacity of the nucleotide excision repair pathway and genomic injury becomes mutagenic and carcinogenic.
- Xeroderma pigmentosum: It is a rare hereditary autosomal recessive disorder characterized by congenital deficiency of nucleotide excision repair DNA.
- These individuals develop skin cancers (basal cell carcinoma, squamous cell carcinoma, and melanoma) due to impairment in the excision of UV-damaged DNA.
2. Ionizing Radiation:
Electromagnetic (X-rays, γ rays) and particulate (α particles, β particles, protons, neutrons) radiations are all carcinogenic.
Cancers Produced by Ionizing Radiation:
- Medical or occupational exposure, for example, leukemia, and skin cancers
- Nuclear plant accidents: Risk of lung cancers.
- Atomic bomb explosion: Survivors of atomic bomb explosion (dropped on Hiroshima and Nagasaki) → increased incidence of leukemias → mainly acute and chronic myelogenous leukemia after about 7 years.
- Subsequently, increased mortality due to solid tumors (for example, Breast, Colon, Thyroid, and Lung).
- Therapeutic radiation: Papillary carcinoma of the thyroid follows irradiation of the head and neck and Angiosarcoma of the liver due to radioactive thorium dioxide used to visualize the arterial tree.
Mechanism Ionizing Radiation:
- Hydroxyl free radical injury to DNA.
- Tissues that are relatively resistant to radiation-induced neoplasia: Skin, bone, and the gastrointestinal tract.
Laboratory Diagnosis Of Cancer
Write a short note on laboratory diagnosis of cancer.
Confirmation of the lesion as neoplastic usually requires cytological and/or histopathological examination of the suspected organ or tissue.
Different laboratory methods available for the diagnosis of malignant tumors are:
1. Morphological Methods
Histopathological Examination:
Histopathological diagnosis is based on the microscopic features of neoplasm and by this method of examination, accurate diagnosis can be made in the majority of cases.
- Clinical data: It should be provided for accurate pathologic diagnosis. Examples:
- Radiation causes changes in the skin or mucosa to mimic changes seen in cancer.
- Sections taken from the site of a healing fracture can mimic osteosarcoma.
- An adequate and representative area of the specimen should be sent.
- Proper fiction.
Frozen Section:
In this method, tissue is frozen and sections are cut by a special instrument called a freezing microtome or cryostat. Its uses are:
- Rapid diagnosis: The frozen section is used for quick histologic diagnosis (within minutes) and is useful for determining the nature of a tumor (benign or malignant) lesion, especially when the patient is still on the operation table.
- Evaluation of the margins of an excised cancer to know whether excision of the neoplasm is complete.
- Demonstration of fat mainly in non-neoplastic lesions.
Various Techniques for Tissue Sampling:
- Needle biopsy: Using a cutting needle, a core of tissue 1 to 2 mm wide and 2 cm long is obtained. The tissue obtained is small and interpretation may be difficult.
- Endoscopy biopsy: It is performed through endoscopy. Usually performed for lesions in gastrointestinal, respiratory, urinary, and genital tracts.
- Incision biopsy: In this representative tissue sample is obtained by incising the lesions.
- Excision biopsy: In this entire abnormal lesion is surgically removed.
Cytological Examination:
It is performed on many tissues and is usually done for identifying neoplastic cells.
Methods of Obtaining Cells:
1. Exfoliative cytology: It is the study of spontaneously exfoliated (shed) cells from the lining of an organ into a body cavity.
- Sources of exfoliated cells: The surface of mucosal or epithelial lining: Cells may be shed naturally or obtained by artificial exfoliation:
-
- Female genital tract:
- Cervix—cells can be obtained by cervical scrape
- Vagina
- Respiratory tract: Sputum and brush cytology by bronchoscopy
- GI tract: Brush cytology by endoscopy
- Urinary tract: Voided urine.
- Female genital tract:
- Body fluids: Usually cells are shed naturally into body fluids.
- Effusions: Pleural, peritoneal, pericardial
- Other fluids: Synovial fluid, CSF, and semen.
-
2. Fine-needle aspiration cytology (FNAC): It involves the aspiration of cells and attendant fluid with a small-bore needle. The smears are prepared and stained, followed by a microscopic examination of cells. It is a widely used, simple, and quick procedure.
- Usual sites: It is most commonly used for the assessment of readily palpable superficial lesions in sites such as the breast, lymph nodes, salivary gland, and thyroid.
- Presently due to imaging techniques, this method is also used for lesions in deep-seated structures (for example, Pelvic lymph, and Lesions in the retroperitoneum, liver, and pancreas).
Advantages of Cytological:
- Less invasive and more rapidly performed
- Prevents surgery and its associated risks
- Extremely reliable and useful.
Method of Examination of Cytological Smears:
- Liquid-based cytology (thin prep): This is a special technique for the preparation of samples that provides uniform monolayered dispersion of cells on smears.
Fixatives Used:
- For Pap smears equal parts of ether and 95% ethanol or 95% ethanol alone
- Coating five as aerosol sprays or with a dropper to the surface of freshly prepared smears
- Pap smears are found immediately in fixative when the smear is still wet and dry smears are found after the smear is air dried.
Cytological Characteristics of Cancer Cells:
- Cancer cells have decreased cohesiveness and show cellular features of anaplasia.
- Cytologically, differentiation can be made between normal, dysplastic, carcinoma in situ, and malignant cells.
Disadvantages of Cytological Examination:
- Diagnosis is based on the features of individual cells or a clump of cells, without supporting evidence of loss of orientation.
- The invasion which is diagnostic of a malignant tumor under histology cannot be assessed by cytology.
Histochemistry and Cytochemistry:
These are stains, which identify the chemical nature of cell contents or their products. H and E staining cannot demonstrate certain specific substances/constituents of cells. This requires some special stains.
Immunohistochemistry:
It is an immunological method of identifying the antigenic component in the cell or one of its components by using specific antibodies. It is widely used in the diagnosis or management of malignant neoplasms.
Uses of Immunohistochemistry:
- To categorize undifferentiated cancers: Many malignant tumors of diverse origins resemble each other and are difficult to distinguish on routine hematoxylin and eosin (H and E) sections.
- To determine the origin of poorly differentiated metastatic tumors: It may be determined by using tissue-specific or organ-specific antigens.
- For prognosis or to select the mode of treatment.
Electron Microscopy:
It helps in the diagnosis of poorly differentiated/undifferentiated cancers, which cannot identify the origin by light microscopy.
Example: Carcinomas show desmosomes and specialized junctional complexes, structures that are not seen in sarcomas or lymphomas.
Common tumor markers:
Flow Cytometry:
It quantitatively measures various individual cell characteristics, such as membrane antigens and the DNA content of tumor cells. Flow cytometry is useful for the identification and classification of tumors of T and B lymphocytes and mononuclear-phagocytic cells.
2. Tumor Markers:
Write short notes on tumor markers with examples.
Tumor markers are products of malignant tumors that can be detected in the cells themselves or in blood and body fluids.
The usefulness of Tumor Markers:
- Detection of cancer, for example, PSA is the most common and useful tumor marker used to screen prostatic adenocarcinoma.
- High levels of PSA are found in the blood of prostatic carcinoma patients but it also may be elevated in benign prostatic hyperplasia.
- Determine the effectiveness of therapy
- Detection of recurrence.
Types of markers:
These may be tumor-associated hormones, oncofetal antigens, specific proteins, mucin and glycoproteins, enzymes, and molecular markers.
3. Molecular Diagnosis:
Molecular diagnosis can be done by different techniques such as the FISH technique and PCR (polymerase chain reaction) analysis.
- Diagnosis of cancer:
- Monoclonal (malignant) vs polyclonal (benign): To differentiate benign (polyclonal) proliferations of T or B cells from malignant (monoclonal) proliferations.
- Chromosomal alterations: Many hematopoietic neoplasms (leukemias and lymphomas) and few solid tumors (for example, Ewing sarcoma) are characterized by particular
translocations that can be detected by the FISH technique or by PCR analysis.
- Prognosis of cancer: Certain genetic alterations are of prognostic value. They can be detected by routine cytogenetics and also by FISH or PCR assays.
- Example of poor prognostic features is amplification of the N-MYC gene deletions of 1p in neuroblastoma and amplification of HER-2/Neu in breast cancer.
- Detection of minimal residual disease: PCR can detect minimal residual disease or the onset of relapse in patients who are treated for leukemia or lymphoma. For example, the detection of BCR-ABL transcripts in treated patients with CML.
- Detection of hereditary predisposition to cancer: Germ-line mutations in many tumor suppressor genes are associated with increased risk for specific cancers. This will help in prophylactic surgery and counseling of relatives at risk. For example, BRCA1, BRCA2, and the RET proto-oncogene.
- For therapeutic decision: It is useful in target therapy. Molecular profiles of tumors: Present methods like DNA microarray technology can measure the expression single gene to all genes in the genome instead of only one gene at a time.
Clinical Aspects Of Neoplasia
Clinical features of malignant tumors.
Both benign and malignant tumors may produce clinical features by their various effects on the host.
Local Effects of Malignant Tumors:
These are due to encroachment on adjacent structures.
- Compression: For example, an adenoma in the ampulla of Vater obstructs the biliary tract.
- Mechanical obstruction: It may be caused by both benign and malignant tumors.
- Example: Tumors may cause obstruction or intussusception in the GI tract.
- Endocrine insufficiency: It is caused by the destruction of an endocrine gland either due to primary or metastatic cancer.
- Ulceration, bleeding, and secondary infections: It may develop in benign or malignant tumors in the skin or mucosa of the GI tract. Example:
- Melena (blood in the stool) in neoplasms of the gut
- Hematuria in neoplasms of the urinary tract.
- Rupture or infarction of tumor.
Functional Effects of Malignant Tumors:
These include:
- Hormonal effects: It may be observed both in benign and malignant tumors of endocrine glands.
- Example: β-cell adenoma of the pancreas may produce insulin → to cause fatal hypoglycemia.
- Paraneoplastic syndromes: Nonendocrine tumors may secrete hormones or hormone-like substances and produce paraneoplastic syndromes (explained below).
- Fever: It is most commonly associated with Hodgkin’s disease, renal cell carcinoma, and osteogenic sarcoma. Fever may be due to the release of pyrogens by tumor cells or IL-1 produced by inflammatory cells in the stroma of the tumor.
Cancer Cachexia (Wasting) of malignant tumors:
It is defined as progressive weight loss accompanied by severe weakness, anorexia, and anemia developing in patients with cancer.
Mechanism of malignant tumors:
It is poorly understood and may be due to TNF and other cytokines, like IL-1, interferon-γ, and leukemia inhibitory factors. They may be produced by macrophages in the tumor or by the tumor cells themselves.
Paraneoplastic Syndromes
Write a short note on the paraneoplastic syndrome.
Malignant tumors invade local tissue, produce metastasis, and can produce a variety of products that can stimulate hormonal, hematologic, dermatologic, and neurologic responses.
Definition of paraneoplastic syndrome: Paraneoplastic syndromes are symptom complexes in cancer patients that are not directly related to mass effects or invasion or metastasis or by the secretion of hormones indigenous to the tissue of origin.
Frequency: Though they occur in 10% to 15% of patients, it is important because:
- May be the first manifestation of an occult neoplasm.
- May be mistaken for metastatic disease leading to inappropriate treatment.
- May present clinical problems which may be fatal.
- Certain tumor products causing paraneoplastic syndromes may be useful in monitoring recurrence in patients who had surgical resections or are undergoing chemotherapy or
radiation therapy.
Some paraneoplastic syndromes, their mechanisms, and the common cancers causing them are listed in the table.
Prognosis
Write a short note on prognostic factors of malignant tumors.
The prognosis of malignant tumors varies and is determined partly by the characteristics of the tumor cells (for example, Growth rate and invasiveness), and partly by the effectiveness of therapy.
Prognostic Indices:
The prognosis and the treatment of a malignant tumor depend on:
1. Tumor type: It is usually identified from the growth pattern of the tumor and its origin by only histopathological examination.
- The prognosis depends on the histological type (for example, squamous cell carcinoma, melanoma, adenocarcinoma, leiomyosarcoma).
- Some tumors like lymphomas require further subclassification into Hodgkin’s and non-Hodgkin’s lymphoma, each of which is then further subclassified by the cell type.
2. Grading of malignant tumors: It is done by histological examination and is mainly based on the degree of differentiation of the tumor cells.
- In general, there is a correlation between histological grade and biological behavior.
- Most grading systems classify tumors into three or four grades of increasing malignancy.
- Low-grade tumors are well differentiated: High-grade ones tend to be anaplastic.
- Shortcomings: Less correlation with behavior: In general, in soft-tissue sarcomas, grading is of less clinical value than staging
- Subjective: Grading is subjective and the degree of differentiation can vary in different areas of the same tumor.
Paraneoplastic syndromes:
3. Staging of tumors: This refers to the extent of the spread of a malignant tumor and is independent of grading. The mode of treatment is determined by the stage of cancer than by its grade.
Write a short note on the staging of cancer
- Criteria: Staging requires both histopathological examinations of the resected tumor and clinical assessment of the patient [including additional non-invasive techniques like computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET)].
- The criteria used for staging vary with different organs. Commonly the staging of cancers is based on:
- Size and extent of local growth of the primary tumor:
- Example: In colorectal cancer, the tumor that has penetrated the muscular and serosa of the bowel is associated with a poorer prognosis than with a tumor restricted to superficial mucosa/submucosa.
- The extent of spread to regional lymph nodes: The presence of lymph node metastases indicates a poor prognosis than without lymph node involvement.
- Presence of or absence of blood-borne (distant) metastases: The presence of bloodborne distant metastases is a bad prognostic sign and is a contraindication to surgical intervention other than for palliative measures.
- Size and extent of local growth of the primary tumor:
TNM Staging Systems:
Grading and staging of cancer.
It is the cancer staging system widely used and it varies for each specific form of cancer. Its general principles are:
- T refers to the size of the primary tumor:
- It is staffed by a number that indicates the size of the tumor or local anatomical extent.
- The number varies according to the organ involved in the tumor. With increasing size, the primary lesion is characterized as T1 to T4. T0 is used to denote an in situ lesion.
- N refers to lymph node status:
- It is staffed by a number to indicate the number of lymph regional nodes or groups of lymph nodes showing metastases.
- N0 would mean no nodal involvement, whereas N1 to N3 would denote the involvement of an increasing number and range of nodes.
- M refers to the presence and anatomical extent of distant metastases:
- M0 signifies no distant metastases, whereas M1 indicates the presence of metastases.
Common Specific Epithelial Tumors
Squamous Papilloma:
- Squamous papillomas are benign neoplasms.
- Sites: Larynx, vulva, and skin.
1. Laryngeal squamous papillomas:
Usually located on the true vocal cords
- Gross: Soft, raspberry-like proliferations rarely more than 1 cm in diameter. They are usually single in adults but may be multiple in children (referred to as juvenile laryngeal papillomatosis)
- Microscopy: Composed of multiple slender, finger-like projections supported by central fibrovascular cores and covered by an orderly stratified squamous epithelium.
2. Vulvar squamous papillomas:
- Located on vulvar surfaces and may be single or numerous (vulvar papillomatosis).
- Microscopy: Exophytic lesions covered by nonkeratinized squamous epithelium.
Adenoma:
It is a benign epithelial tumor arising from glandular epithelium, although it may
or may not form glandular structures.
Examples:
1. Follicular adenoma of the thyroid: It usually shows microscopically numerous tightly packed small glands.
2. Adenomas of GIT: Adenomas can be classified as tubular, tubulovillous, or villous.
- Tubular Adenomas (Adenomatous Polyps): They constitute two-thirds of the adenomas of the large intestine.
- Gross: Appear as small, smooth-surfaced, pedunculated polyps usually less than 2 cm in diameter. Tubular adenoma over 2 cm has a higher risk of invasive carcinoma.
- Microscopy: Consists of closely packed small rounded or tubular glands. embedded in a stroma (increase in the number of glands and cells per unit area compared to the normal mucosa).
- Villous Adenomas (Villous Papilloma):
- They constitute one-tenth of colonic adenomas and are predominantly found in the rectosigmoid region.
- Gross: Large, broad-based, sessile, elevated lesions with cauliflower-like surface. Most are over 2 cm but may be as large as 10 to 15 cm in diameter.
- Microscopy: Composed of thin, long, fingerlike projections (papillary, crown-like growth), which superficially resemble the villi of the small intestine.
- The lining epithelium shows dysplasia similar to tubular adenomas. However, villous adenomas (larger than 2 cm) likely contain foci of carcinoma more commonly than tubular adenomas.
- Tubulovillous Adenomas:
- They show a mixture of both tubular and villous elements.
- Polyps with more than 25% and less than 75% villous component are called as tubulovillous.
Squamous Cell Carcinoma
Write a short note on squamous cell carcinoma of the skin.
- The second most common tumor arising on sun-exposed sites.
- Sex: More common in men than in women.
- Clinical presentation: Appear as sharply defied, red, scaling plaques.
- Sites: Skin, oral cavity, larynx, penis, cervix, esophagus, lung, and sites wherever there is squamous epithelium.
Etiology and Pathogenesis of squamous cell carcinoma :
Risk Factors:
- Exposure to UV light: It may produce DNA damage and is the most important cause of squamous cell carcinoma of the skin. The risk is proportional to the degree of lifetime sun exposure.
- Chronic immunosuppression: It may be due to chemotherapy or organ transplantation and may contribute to carcinogenesis.
- The immunosuppression reduces host surveillance and increases the susceptibility of keratinocytes to infection and transformation by oncogenic viruses.
- These oncogenic viruses include human papillomavirus (HPV) subtypes 5 and 8.
- Apart from damaging DNA, sunlight can cause a defect in cutaneous immunity by reducing the immune surveillance function of epidermal Langerhans cells.
- Other risk factors:
- Industrial carcinogens: Tars and oils.
- Chronic non-healing ulcers: For example, chronic osteomyelitis.
- Old burn scars (for example, Marjolin’s ulcers).
- Ingestion of arsenicals.
- Ionizing radiation.
- Tobacco and betel nut chewing in the oral cavity.
Genetics of Squamous Cell Carcinoma:
- Mutations in tumor suppressor p53 gene:
- UV light present in the sunlight damages DNA.
- Mutations in DNA repair genes:
- Xeroderma pigmentosum is a disorder characterized by inherited mutations in DNA repair genes, and these patients are susceptible to squamous cell carcinoma.
- Other genes: Dysregulated RAS signaling may also be responsible.
Morphology of Squamous Cell Carcinoma:
Squamous cell carcinoma in situ:
- Characterized by cells with atypical (enlarged and hyperchromatic) nuclei involving all levels of epidermis.
- No invasion through the basement membrane of the dermo-epidermal junction.
Invasive squamous cell carcinoma:
- Gross: Invasive lesions are more advanced lesions, which appear as nodular growth and may ulcerate. The ulcer is surrounded by a wide, elevated, indurated border.
- Microscopy: The tumor consists of irregular masses of epidermal cells that proliferate downward into the dermis.
They show variable degrees of differentiation, ranging from well to poorly differentiated.
- Well-differentiated squamous cell carcinoma: They are composed of polygonal squamous tumor cells arranged in orderly lobules and produce large amounts of keratin.
- Some of this keratin form epithelial or squamous pearls and are characteristically seen in well-differentiated tumors.
- Moderately differentiated squamous cell carcinoma: They consist of anaplastic squamous cells, which show single-cell keratinization (dyskeratosis). It may be associated with areas of geographic necrosis.
- Poorly differentiated squamous cell carcinoma: They consist of highly anaplastic cells. Poorly differentiated tumors may require immunohistochemical stains for keratins to confirm the diagnosis.
Basal Cell Carcinoma:
Write a short note on basal cell carcinoma (rodent ulcer) of the skin.
Basal cell carcinoma is the most common, slow-growing invasive cancer that rarely metastasizes.
- Sites: Occur at sun-exposed sites and in fair-skinned people. The usual site is above a line drawn from the angle of the mouth to the pinna of the ear.
- Origin: Basal cell carcinoma derives its name from the cytological similarity of the tumor cells to the normal basal cells of the epidermis. It is believed to be primitive ‘adnexal’ carcinomas probably of indubitable hair follicle derivation.
Etiology and Pathogenesis of Basal cell carcinoma:
The incidence of basal cell carcinoma is also higher in patients with immunosuppression and inherited defects in DNA repair such as xeroderma pigmentosum.
Genetics of Basal Cell Carcinoma:
1. Mutation in tumor suppressor gene:
- Mutation in PTCH: PTCH acts as a tumor suppressor gene: Mutations of genes belonging to the PTCH signaling pathway are important for the development of both common sporadic and inherited forms of basal cell carcinoma.
- p53 mutations: They occur in 40 to 60% of cases.
2. Defect in DNA repair genes: Xeroderma pigmentosum is a disorder of DNA repair, associated with an increased incidence of basal cell carcinoma.
Clinical Presentation Basal cell carcinoma:
- Appear as pearly papules often containing prominent, dilated subepidermal blood vessels.
- Some tumors may contain melanin and may resemble melanocytic nevi or melanomas.
- Advanced tumors may ulcerate, and locally invade and erode the underlying bone or
facial sinuses like a rodent and are known as rodent ulcers.
Morphology Basal cell carcinoma:
- Gross:
- Appearance varies and may be nodular, ulcerative, superficial, or erythematous.
- Nodulo-ulcerative basal cell carcinoma is the most common type and presents as a nodule that increases slowly in size and undergoes central ulceration.
- A typical lesion consists of a slowly enlarging ulcer surrounded by a pearly, rolled border.
- This represents the so-called rodent ulcer (which erodes the underlying structures similar to a rodent).
Microscopy Basal cell carcinoma:
- Tumor cells: They resemble the normal basal cell layer of the epidermis and are referred to by some as basaloma (germinative) cells. The tumor cells are deeply basophilic epithelial cells and have a large, oval, or elongated nucleus with a narrow rim of cytoplasm.
- Arrangement: Tumor cells are arranged in nests are attached to the epidermis and protrude into the subjacent papillary dermis.
- Peripheral palisading: At the periphery of each nest, the columnar cells are arranged radially with their long axes in parallel alignment known as peripheral palisading.
- Clefting artifact between tumor islands and adjacent stroma: It may sometimes help distinguish
- BCC from other adnexal neoplasms displaying basaloid cell proliferation.
Two patterns of growth:
- Multifocal growths: These tumors originate from the epidermis and extend over several square centimeters or more of the skin surface (multifocal superficial type).
- Nodular lesions: These tumors grow deeply downward into the dermis as cords and islands of variably basophilic cells with hyperchromatic nuclei.
Melanoma:
Write a short note on malignant melanoma.
Melanoma is a relatively common neoplasm.
- Site:
- Skin: It is the most common site and may develop in the trunk, leg, face, sole, palm and nail beds.
- Other sites: Oral and anogenital mucosal surfaces, esophagus, leptomeninges, eye, and the substantia nigra.
- Cell of origin: Melanocytes.
Etiology and Pathogenesis of malignant melanoma:
Predisposing Factors
1. Sun Exposure:
- Melanomas most commonly develop on sun-exposed surfaces, particularly the upper back in men and the back and legs in women.
- Lightly-pigmented individuals are at greater risk than darkly-pigmented individuals.
2. Inherited Genes:
About 10 to 15% of melanomas are familial and the genetic abnormalities are:
- Mutations in tumor suppressor gene:
- Mutations in CDKN2A gene: It is observed in familial as well as in a few sporadic melanomas.
- Mutations in the RB gene: These are common in both familial and sporadic melanomas.
- Silencing of PTEN gene.
- Oncogene activation: It may occur by mutations in proteins involved in signal transduction. Aberrant increases in RAS signaling may occur due to mutations in RAS or BRAF, which promote cell growth and survival.
Morphology of malignant melanoma:
Write a short note on the morphology of malignant melanoma.
Growth phases:
1. Radial growth phase: During this phase, the melanoma spreads horizontally within the epidermis and superficial dermis.
- It represents the initial stage where the tumor cells cannot metastasize.
- Tumors in the radial growth phase fall into different clinicopathologic classes.
- Lentigo maligna: It usually presents as an indolent lesion on the face of older men.
- The tumor may remain in the radial growth phase for several decades.
- Superficial spreading: It is the most common type of melanoma, and usually involves the skin exposed to the sun.
- Acral/mucosal lentiginous melanoma: It is not related to sun exposure and is usually seen in the palm, sole, or mucosa.
2. Vertical growth phase: After a variable and unpredictable period, melanoma from the radial phase develops a vertical growth phase.
Characteristics: During this phase:
- Tumor cells invade downward into the deeper dermis.
- Melanoma may appear as a nodule and develop a clone of cells with metastatic potential.
- Maturation is absent from the deep invasive portion of melanoma.
- The risk of metastasis correlates with the depth of invasion, which is the distance from the superficial epidermal granular cell layer to the deepest intradermal tumor cells.
- This measurement is known as the Breslow thickness.
Microscopy of malignant melanoma:
- Tumor cells: They have a similar appearance in both the radial and vertical phases of growth.
- Size: Tumor cells are usually larger than normal melanocytes or nevus cells found in melanocytic nevi.
- Nuclei: They are large with irregular contours, clumping of chromatin at the periphery of the nuclear membrane, and prominent red (eosinophilic) nucleoli. Mitotic are often seen.
- The pattern of growth: Tumor cells are arranged in solid masses, sheets, islands, etc. Tumor invades the upper epidermis as well as the deeper dermis.
- Melanin pigment: It is seen in melanoma. Melanoma, which does not show the pigment, is known as amelanotic melanoma. Melanin is present in the cytoplasm as uniform brown fine granules.
Clinical Features of malignant melanoma:
- Melanoma of the skin is usually asymptomatic but may present with itching or pain at the site of the lesion.
- Changes in pigmented lesions: These are the most important clinical signs of melanoma and include:
- Color: Unlike benign nevi, melanomas show color variations, ranging from shades of black, brown, red, dark blue, and gray.
- Size: The majority are larger than 10 mm in diameter at the time of diagnosis. But, if the pigmented lesion is greater than 6 mm in diameter, any change in appearance and new onset of itching or pain should raise the suspicion of malignancy.
- Shape: The borders of melanomas are irregular and often notched, whereas they are smooth, round, and uniform in melanocytic nevi.
Adenocarcinoma of malignant melanoma:
- Carcinoma arising from secretory/mucosal epithelial lining glands or ducts or organs is called adenocarcinoma.
- Sites: Stomach, colorectal region, gallbladder, pancreas, uterus, prostate, and other in glandular organs.
- Gross appearance varies with the site of adenocarcinoma.
- The tumor cells contain abundant mucin which expands the cytoplasm and pushes the nucleus to the periphery creating a signet-ring cell appearance.
- If the signet-ring cells constitute more than 50% of the tumor, it is classified as signet-ring cell carcinoma.
Microscopy of malignant melanoma:
- Adenocarcinoma may be well-differentiated, moderately or poorly differentiated.
- Most of the tumors show glands of variable size and configuration separated by a moderate amount of stroma. Mitotic are usually abundant.
- Poorly differentiated carcinoma shows only a few glands.
- Mucinous adenocarcinomas: They secrete abundant mucin accumulate within the intestinal wall and are associated with poor prognosis.
- Signet-ring carcinoma: The tumor cells contain abundant mucin which expands the cytoplasm and pushes the nucleus to the periphery creating signet-ring cell and Appearance.
Mesenchymal Tumors
1. Fibroma:
A benign tumor arising in fibrous tissue is called a fibroma. True fibromas are uncommon in soft tissue. A combination of fibrous and other mesenchymal tissue is more often seen.
These include neurofiroma, firomyoma, dermatofiroma and firolipoma.
- Oral cavity: Fibroma is common in the oral mucosa. It is a reactive lesion rather than a neoplastic process.
- It is called as irritation fibroma (traumatic fibroma or focal fibrous hyperplasia).
- Gross: It occurs as a submucosal nodular mass primarily on the buccal mucosa along the bite line or the gingiva.
- Microscopy: It shows fibrous connective tissue stroma. It is thought to be a reactive proliferation caused by repetitive trauma.
- Ovary: Fibromas of ovaries are relatively common benign tumors composed of fibroblasts. .They constitute about 4% of all ovarian tumors.
- Gross: They are predominantly unilateral in about 90% of cases. They are usually solid, spherical, encapsulated, gray-white tumors.
- Microscopy: They consist of well-differentiated fibroblasts and a scant interspersed collagenous stroma.
- Dermis: Benign fibrous histiocytoma (dermatofibroma) constitutes a heterogeneous family of benign dermal neoplasms of uncertain lineage.
- They are usually seen in adults and often on the legs of young and middle-aged women. They consist of a mixture of both fibrous tissue and histiocytes.
2. Fibrosarcoma:
Fibrosarcomas are very rare tumors because many of the tumors earlier diagnosed as fibrosarcomas presently belong to a group of tumors known as fibrous histiocytomas.
Fibrosarcoma is a slow-growing malignant tumor arising from fibrous tissue. It is often found between the 4th to 7th decades of life.
Most commonly they occur in the lower extremity (thigh and around the knee), upper extremity, trunk, head and neck, and retroperitoneum.
- Gross: They are circumscribed gray-white, film, and lobulated tumors. The cut section has a soft, fish fish-like appearance. Areas of hemorrhage and necrosis are usually seen.
- Microscopy: The tumor consists of spindle-shaped fibroblasts arranged in intersecting fascicles.
- Well-differentiated fibrosarcomas show characteristic herring-bone patterns (herring = a type of sea-fish).
- Poorly differentiated fibrosarcomas show pleomorphic fibroblasts with frequent mitosis.
Tumors of Adipose Tissue:
1. Lipoma:
- Lipoma is the most common benign tumor of fat.
- It is the most common soft tissue tumor in adulthood.
- Occur most often during the 4th to 5th (middle adulthood) decades of life.
- Lipomas are usually single, soft, mobile painless masses.
- Site: Usually arises in the subcutaneous tissues of the proximal extremities, neck, back, shoulder, and trunk. Infrequently, lipomas are large and intramuscular.
- Gross: It is usually a well-encapsulated (maybe poorly circumscribed), small,
round to oval mass. The cut surface is soft, yellow, greasy, and often lobulated. - Microscopy: It shows lobules of mature adipocytes separated by delicate fibrous
septa. - A thin fibrous capsule is usually found surrounding the tumor.
2. Liposarcoma:
Liposarcoma is one of the most common soft tissue sarcomas of adulthood.
- Age: It occurs mainly during the 5th to 6th decades of life.
- Sites: Deep soft tissues of the proximal extremities and in the retroperitoneum.
- Gross: Liposarcomas appear as nodular masses of 5 cm or more in diameter. Tumors are usually appearing circumscribed but infiltrate into the surrounding tissue. The cut section show a gray-white to yellow color with a myxoid and gelatinous appearance.
- Microscopy: The cell required for the diagnosis of liposarcoma is lipoblast. These cells may be uni vacuolated or multivacuolated and uninucleated or multinucleated.
Liposarcomas are histologically divided into four morphologic subtypes:
- Well-differentiated liposarcoma: Contains adipocytes with scattered atypical spindle cells and lip blasts.
- Myxoid liposarcoma: Most common histological subtype. Contains abundant basophilic extracellular matrix, arborizing capillaries (chicken-wire pattern), and primitive cells at various stages of adipocyte differentiation reminiscent of fetal fat.
- Round cell liposarcoma: It consists of uniform, round to oval cells with central hyperchromatic nuclei. The cytoplasm shows multiple vacuoles.
- Pleomorphic liposarcoma: It is highly undifferentiated/anaplastic liposarcoma and consists of sheets of anaplastic cells, bizarre nuclei, and variable amounts of immature adipocytes (lip blasts).
The behavior of Adipose Tissue:
- All histological types of liposarcoma recur locally and often repeatedly unless adequately excised.
- Well-differentiated liposarcoma is relatively indolent; the myxoid/round cell liposarcoma is intermediate in its malignant behavior.
- The pleomorphic variant usually is aggressive and frequently metastasizes.
Leave a Reply