Neoplasia

INTRODUCTION TO NEOPLASIA 

DEFINITION An abnormal tissue mass whose growth exceeds and is uncoordinated with that of adjacent normal tissue and persists after cessation of the stimuli that provoked it.

CLASSIFICATION

Classification according to their tissue of origin :1) epithelial (neoplasia of lining tissues), 2) mesenchymal (neoplasia of connective tissue derivatives), 3) germ cell (neoplasia of undifferentiated stem cells ,sperm,

Benign Neoplasm 

A neoplasm that grows without invading adjacent tissue or spreading to distant sites. It is usually fairly well-circumscribed due to the lack of invasion of surrounding tissues

Malignant Neoplasm

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A neoplasm that invades the surrounding normal tissue and usually spreads to distant sites given sufficient time.

Nomenclature 

Neoplasms have two components 1. Parenchyma= neoplastic cells  decides behavior & Pathologic consequences 1. Stroma= Supportive ( connective tissue & Vessels)  Determines Growth & Evolution  Soft & fleshy neoplasm Scant stroma

Neoplasia- Nomenclature Benign Mesenchymal 

Easy =Cell origin + oma  Chondro + Oma = Chondroma {Cartilage}  Fibro + Oma = Fibroma {Fibroblast}  Lipo + Oma = Lipoma {Fat/ lipocyte / adipocyte}

Epithelial  Not easy •

Adenoma  benign epithelial tumor derived from or present with glandular pattern • Papilloma  finger-like or warty projections from the epithelial surfaces (MC - skin) • Polyp  fist-like projection from mucosal epithelial surfaces( MC colon) • Cystadenomas: forms large cystic mass (ovaries) • Papillary cystadenoma: papillary patterns that protrude into the cystic spaces (ovaries)

Neoplasia- Nomenclature Malignant Mesenchymal

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Sarcoma

Greek = “fleshy” ( little stroma)  Chondro + sarcoma = Chondrosarcoma {Cartilage}  Fibro + sarcoma = Fibrosarcoma {Fibroblast}  Lipo + sarcoma = Liposarcoma {Fat/ lipocyte / adipocyte}  Rhabdomyo +sarcoma = Rhabdomyosarcoma {striated muscle}

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Epithelial 

carcinoma (any germ layer) Adenocarcinoma glandular growth pattern  Squamous cell carcinoma squamous cell differentiation  specify organ of origin Renal cell adenocarcinoma, Bronchogenic  Undifferentiated/ poorly differentiated Can’t determine tissue of origin  Mixed tumors Pleomorphic adenoma  Divergent differentiation of a single germ line of parenchymal cells (salivary gland)  Teratoma  From Totipotential cells (gonads), > one germ layer { Dermoid cyst  ovary} 

Malignant neoplasias with benign suffixes Lymphoma Mesothelioma Myeloma Astrocytoma Glioma

Benign -Epithelial A

B

Benign

Mesenchymal Leiomyoma

Epithelial Adenoma = thyroid

Pleomorphic adenoma - Salivary gland

cartilage

Epithelial components

Teratoma

Dysplasia 

Atypical proliferation of cells characterized by nuclear enlargement and failure of maturation and differentiation, short of malignancy.

Anaplasia

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Loss of differentiation

(Carcinoma in situ (cis 

Full-thickness dysplasia extending from the basement membrane to the surface of the epithelium. Applicable only to epithelial neoplasms. If the entire lesion is no more advanced than CIS, then the risk of metastasis is zero. This is because there are no blood vessels or lymphatics within the epithelium above the basement membrane.

Carcinoma Squamous cell carcinoma

Carcinoma in-situ

Differentiation The tissue type represented by the .tumor Well-differentiated tumors resemble identifiable tissue types, while poorly differentiated tumors may only be identifiable by the expression of cell markers or by extremely focal and subtle histologic and/or cytologic findings.

Metastasis 

Spread of tumor to distant sites by lymphatic, hematogenous routes, or seeding of body cavities.

Local Invasion 

Growth into the surrounding tissue by direct expansion.

DIFFERENCES Features Boundaries Surrounding tissues Size Growth Capsule Degeneration Recurrence Fixity

Benign Malignant Encapsulated Irregular Often Usually invaded compressed Usually small Often large Slow & Rapid & infiltrating expanding Present Absent Rare Common Not common Common Absent Present

DIFFERENCES Features Pattern

Benign Usually resemble Basal polarity Retained Pleomorphism Not present N/C ratio Normal Anisonucleosis Absent Hyperchromati Absent sm Mitosis Typical mitosis

Malignant Poor resemblence Lost Often present Increased Present Present Atypical &

DIFFERENCES Features Benign Malignant Tumour giant Without nuclear With nuclear cells atypia atypia Cytoplasm Normal Decreased or lost constituents Function Well maintained Lost or abnormal Growth rate Local invasion

Slow Compreses the surrounding .tissue

Rapid Infiltrates & invades the tissues

Malignant tumors Feature

Sarcoma

Carcinoma

Arise from mesenchymal tissue Arise from epithelial tissue Origin Usually larger since harder to Usually smaller since easier Mass size detect them in deep tissue. to detect on surface Takes longer to diagnose Time of diagnosis Goes directly to vascular Route of system/ Blood vessels (i.e. Metastasis blood) Worse prognosis Prognosis

Takes shorter period of time to diagnose from onset Goes through lymphatics first – longer route to vascular system Good/worse

Malignant tumors Mesenchymal Sarcoma

Epithelial Adenocarcinom a

Hamartoma      

May be mistaken for a true tumour Focal , circumscribed overgrowth. Improper proportions of tissue. No continuous overgrowth. Tumour - like malformation. Tissues of which is composed are present in that area.

Choristoma  

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Similar to hamartoma. Tissues of which is composed are not normally present in that area. Eg :-adrenal gland tissue in urinary bladder.

MOLECULAR BASIS OF NEOPLASM

Carcinogenesis Induction of tumor is carcinogenesis & agents which can induce tumor are carcinogens. Carcinogens can be:1. Chemical carcinogens. 2. Physical carcinogens. 3. Hormonal carcinogens. 4. Biologic carcinogens.

Chemical carcinogens: These can be: Direct acting-which require no prior activation.  Indirect acting- which require prior activation.

Physical carcinogens:It includes 1.Radiation 2. Non radiation carcinogens. For e.g. ultraviolet rays, ionizing rays, chronic irritation etc.

Hormonal carcinogens:Certain hormones e.g. oral contraceptives and anabolic steroids increase the risk of developing benign and malignant tumors. Hormone sensitive tissues are breast, endometrium, myometrium, thyroid, liver and prostate.

Biologic carcinogens:It includes 1.Viral carcinogens, e.g. HPV, EBV, HBV etc. 2.Parasitic carcinogens, e.g. schistosomiasis. 3.Bacterial carcinogens, e.g. Helicobacter pylori.

Rate of growth The growth rate of tumors correlates with their level of differentiation, and thus malignant tumors grow more rapidly than do the benign lesions, though examples of benign tumors with a higher growth rate also exist.

The rate of growth of benign as well as malignant tumors is therefore not constant over time. Various factors govern the rate of growth of tumors, e.g.:  Hormone dependence  Adequacy of blood supply  Unknown influences.

For e.g.: Leiomyomas of uterus are benign smooth muscle tumors. These may show no significant increase in size or may even undergo atrophy post menopause, but, may enter a rapid growth phase during pregnancy, under the influence of circulating steroid hormones , particularly estrogen.

Clinical picture of leiomyoma uterus

An abrupt increase in size and disseminating behaviour of malignant neoplasm is believed to be the result of emergence of aggressive subclone of transformed cells.

Modes of spread Neoplasia can spread by:1. Local invasion 2. Metastasis.

Local invasion:Almost all benign tumors * grow as cohesive expansile masses. * remaining localized to site of origin. * do not have capacity to infiltrate, invade or metastasize to distant sites.

As these expand and grow slowly, they develop a rim of compressed connective tissue called the fibrous capsule.  Separates

tumor from host tissue.  Derived from native tissue.  Makes neoplasm discrete, readily palpable & easily movable mass that can be surgically enucleated.

Benign tumor of vertebral column.

There are exceptions for e.g. hemangioma, which is a neoplasm of tangled blood vessels n are often unencapsulated & may appear to permeate the site of origin.

While benign tumors are non invasive, the growth of cancers is accompanied by progressive infiltration, invasion & destruction of surrounding tissues. Sometimes the slowly expanding malignant tumors may develop an apparent capsule.

Histology of this capsule shows tiny crab like feet penetrating the margins and infiltrating adjacent tissues.

Thus, malignant tumors are invasive, and recognize no anatomical boundaries, making surgical resection difficult. Therefore, it is necessary to remove a considerable margin of apparently normal tissue around infiltrative neoplasm.

Invasiveness is one of the reliable factors differentiating benign and malignant tumors. Preinvasive stage of tumors in which they do not invade the basement membrane is termed as carcinoma in situ.

:-Metastasis Metastasis are tumor implants discontinuous with the primary tumor.

Metastasis in progress

Metastasis alone mark s a tumor as malignant. Almost all cancers metastasize . Exceptions are few for e.g. 1. Glioma, malignant neoplasm of glial cells of CNS.

2. Basal cell carcinoma, locally invasive neoplasm also known as rodent ulcer but does not metastasize

In general, the more aggressive, the more rapidly growing & the larger the primary neoplasm is the greater are the chances of metastasis. Approximately 30% of newly diagnosed patients of solid tumors present with metastasis. Presence of metastasis reduces the cure rate.

Pathways of spread Dissemination of tumor cells occurs by: Lymphatic spread.  Hematogenous spread.  Direct seeding of body cavity/surfaces.

Direct transplantation of tumor cells, for e.g. by surgical instruments, may occur theoretically, but is considered an artificial mode of dissemination .

Lymphatic spread:It is the most common pathway for initial dissemination of carcinomas. Regional lymph nodes serve as an effective barrier to further dissemination of tumor cells, at least for sometime. The cells may be destroyed by tumor specific immune response.

This drainage of tumor cell debris or tumor antigens or both may induce reactive changes in the nodes.

The enlargement of nodes may be caused by:1. Spread and growth of cancer cells 2. Reactive hyperplasia Thus, nodal enlargement in proximity to a cancer , does not necessarily mean dissemination of primary lesion

The pattern of lymph node involvement follows the natural routes of drainage.

For e.g. carcinomas of lung arising in major respiratory passage metastasize to prehilar tracheobronchial and mediastinal lymph nodes.

Skip metastasis is also sometimes seen i.e. bypassing of a lymph node. This occurs due to:1.Venous lymphatic anastomoses in the area. 2.Inflammation obliterated channels. 3.Radiation obliterated channels.

.Diagrammatic representation of lymphatic metastasis

Hematogenous spread:It is typical of sarcomas but may also be seen in carcinomas. It can spread by two ways:-

1.Arterial

spread. 2.Venous spread.

Arterial spread:Arteries have thicker walls than veins, and thus are less readily penetrated. Arterial spread may however occur when tumor cells pass through the pulmonary capillary beds, arteriovenous shunts or when pulmonary metastasis themselves gives rise to additional tumor emboli.

Venous spread:The cells follow the venous drainage. Liver &lungs are most commonly involved secondarily in such hematogenous dissemination. All portal areas drainage flows to the liver, and all caval areas drainage flows to the lungs.

Certain cancers have the propensity for invasion of veins. For e.g. renal cell carcinoma invades branches of renal vein & renal vein itself grows in snake like fashion to IVC & may reach right heart.

.Hematogenous spread

Direct seeding of body cavities & surfaces:Seeding occurs whenever a neoplasm penetrates into natural OPEN FIELDS. Mostly it is the peritoneal cavity but any cavity may be involved.

Direct seeding of body cavity is common in carcinomas arising in the ovaries, where the peritoneal surface gets coated with a heavy layer of cancerous glaze.

METASTATIC CASCADE  Invasion

of ECM & vascular dissemination.  Homing of tumor cells.

INVASION OF ECM 

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Detachment of tumor cells from each other. Local degradation of the basement membrane & interstitial connective tissue. Changes in attachment of tumor cells to ECM proteins. Migration of tumor cells.

Detachment of tumor cells from each other 

Loosening of tumor cells due to loss of function of E-cadherins & beta catenin.

Local degradation of the basement membrane & interstitial connective tissue 

Tumor cells secrete proteolytic enzymes or induce stromal cells to eloborate proteases (MMPs, cathepsin D, urokinase plasminogen activator).

Changes in attachment of tumor cells to ECM proteins 

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Tumor cells are resistant to apoptosis. Matrix itself is modified in ways that promote invasion & metastasis.

Migration of tumor cells 

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Tumor cells are propelled through the degraded basement membrane & zones of matrix proteolysis. Such movement is potentiated by: tumor cellderived cytokines (AMF) & stromal cells derived paracrine effectors.

VASCULAR DISSEMINATION & HOMING OF TUMOR CELLS

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In the bloodstream, some tumor cells form emboli by aggregating & adhering to circulating leukocytes, particularly platelets. Extravasation of free tumor cells or tumor emboli involves adhesion to the vascular endothelium, followed by egress through the basement membrane into the organ parenchyma by mechanisms similar to those involved in invasion.

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The site of extravasation & organ distribution of metastasis generally can be predicted by the location of the 1o tumor & its vascular or lymphatic drainage. After extravasation, tumor cells are dependent on a receptive stroma for growth. Thus, tumors may fail to metastasize to certain target tissues because they present a nonpermissive growth environment.