Neoplasia ..

Neoplasia .

Neoplasia Upon completion of these lectures, the student should:
Define a neoplasm. Contrast neoplastic growth with hyperplasia, metaplasia, and dysplasia. Know the basic principles of the nomenclature of benign and malignant processes. Define and use in the proper context: Adenoma. Papilloma. Polyp. Cystadenoma. Carcinoma. Adenocarcinoma. Sarcoma. Teratoma. Blastoma. Hamartoma.

Neoplasia Cancer is one of the leading causes of death worldwide.
Emotional and physical suffering by the patient. Different mortality rate ….. Some are curable Others are fatal

Neoplasia Neoplasia = new growth Neoplasm = tumor Tumor = swelling
The study of tumors = Oncology Oncos = tumor + ology = study of

Neoplasia Definition: is an abnormal mass of tissue,
the growth of which is uncoordinated with that of normal tissues, and that persists in the same excessive manner after the cessation of the stimulus which evoked the change“ With the loss of responsiveness to normal growth controls Different from hyperplasia, metaplasia and dysplasia.

Neoplasia Classification Benign malignant

Neoplasia Benign tumors : Will remain localized
Cannot spread to distant sites Generally can be locally excised Patient generally survives

Neoplasia Malignant neoplasms:
Can invade and destroy adjacent structure Can spread to distant sites Cause death (if not treated )

Neoplasia All tumors have two basic components:
Parechyma: made up of neoplastic cells Stroma: made up of non-neoplastic, host-derived connective tissue and blood vessels The parenchyma: Determines the biological behavior of the tumor From which the tumor derives its name The stroma: Carries the blood supply Provides support for the growth of the parenchyma

Neoplasia Nomenclature Benign tumors: prefix + suffix
Type of cell + (-oma)

Neoplasia Examples: Benign tumor arising in fibrous tissue:
Fibro + oma = Fibroma Benign tumor arising in fatty tissue: Lipo + oma = lipoma

Neoplasia Benign tumor arising in cartilage chondro + oma = chondroma
Benign tumor arising in smooth muscle Leiomyo + oma = leiomyoma Benign tumor arising in skeletal muscle Rhabdomyo + oma = rhabdomyoma

Neoplasia epithelial benign tumors are classified on the basis of :
The cell of origin Microscopic pattern Macroscopic pattern

Neoplasia Adenoma : benign epithelial neoplasms producing gland pattern….OR … derived from glands but not necessarily exhibiting gland pattern Papilloma : benign epithelial neoplasms growing on any surface that produce microscopic or macroscopic finger-like pattern

Adenoma

Papilloma

Neoplasia Polyp : a mass that projects above a mucosal surface to form a macroscopically visible structure. e.g. - colonic polyp - nasal polyp

Neoplasia Examples : Respiratory airways: Bronchial adenoma
Renal epithelium: Renal tubular adenoma Liver cell : Liver cell adenoma Squamous epithelium: squamous papilloma

Neoplasia Malignant tumors arising from epithelial origin : CARCINOMA
Squamous cell carcinoma Renal cell adenocarcinoma cholangiocarcinoma

Carcinomas arising from any epithelium of the body that exhibit squamous differentiation are termed squamous cell carcinoma.

Neoplasia Malignant tumors:
Malignant tumor arising in mesenchymal tissue : SARCOMA From fibrous tissue: Fibrosarcoma From bone : Osteosarcoma From cartilage : chondrosarcoma

Osteosarcoma

Papillary Cystadenocarcinoma of the Ovary
Nomenclature other descriptive terms may be added such as: Papillary Cystadenocarcinoma of the Ovary

Neoplasia Exceptions Melanoma ( skin ) Mesothelioma (mesothelium )
Seminoma ( testis ) Lymphoma ( lymphoid tissue ) See table 6 – 1 ( Robbin’s )

Nomenclature of tumors
Tissue of Origin Benign Malignant Composed of One parenchymal cell Type Connective tissue and derivatives Fibroma Lipoma Chondroma Osteoma Fibrosarcoma Liposarcoma Chondrosarcoma Osteogenic sarcoma Endothelial and related tissues Blood vessels Lymph vessels Synovium Mesothelium Brain coverings Hemangioma Lymphangioma Meningioma Angiosarcoma Lymphangiosarcoma Synovial sarcoma Mesothelioma Invasive meningioma

Tissue of Origin Benign Malignant Blood cells and related cells Hematopoietic cells Lymphoid tissue Muscle Smooth Striated Leiomyoma Rhabdomyoma Leukemias Lymphomas Leiomyosarcoma Rhabdomyosarcoma Epihelial tumors Stratified squamous Basal cells of skin or adnexa Epithelial lining Glands or ducts Squamous cell papilloma Adenoma Papilloma Cystadenoma Squamous cell carcinoma

Tissue of Origin Benign Malignant Epihelial tumors Stratified squamous Basal cells of skin or adnexa Epithelial lining Glands or ducts Squamous cell papilloma Adenoma Papilloma Cystadenoma Squamous cell or epidermoid carcinoma Basal cell carcinoma Adenocarcinoma Papillary carcinoma Cystadenocarcinoma

Tissue of Origin Benign Malignant Respiratory passages Neuroectoderm Renal epithelium Liver cells Urinary tract epithelium (transitional) Placental epithelium (trophoblast) Testicular epithelium (germ cells) Tumours of melanocytes Bronchial adenoma Nevus Renal tubular adenoma Liver cell adenoma Transitional cell papilloma Hydatidiform mole Bronchogenic carcinoma Bronchial adenoma (carcinoid) Malignant melanoma Renal cell carcinoma Hepatocellular carcinoma Transitional cell carcinoma Choriocarcinoma Seminoma Embryonal carcinoma

Tissue of Origin Benign Malignant More Than One Neoplastic Cell Type- Mixed Tumors, Usually Derived From One Germ Layer Salivary glands Pleomorphic adenoma (mixed tumor of salivary origin) Malignant mixed tumor of salivary gland origin Breast Fibroadenoma Malignant cystosarcoma phyllodes

Tissue of Origin Benign Malignant More Than One Neoplastic Cell Type Derived From More Than One Germ Layer- Teratogenous Totipotential cells in gonads or in embryonic rests Mature teratoma, dermoid cyst Immature teratoma, teratocarcinoma

Neoplasia Based on the biological behavior :
Benign and malignant Based on the cell of origin : One neoplastic cell type : lipoma, adenocarcinoma More than one neoplastic cell type : fibroadenoma More than one neoplastic cell type derived from more than one germ-cell layer: teratoma Derived from embryonic tissue: blastoma (could be benign e.g. osteoblastoma, or malignant e.g. neuroblastoma)

Lipoma

Fibroadenoma

Teratoma

Neoplasia Teratoma: Teratoma contains recognizable mature or immature cells or tissues representative of more than one germ-cell layer and some times all three. Teratomas originate from totipotential cells such as those normally present in the ovary and testis.

Neoplasia Such cells have the capacity to differentiate into any of the cell types found in the adult body. So they may give rise to neoplasms that mimic bone, epithelium, muscle, fat, nerve and other tissues. Most common sites are: ovary & testis

Neoplasia If all the components parts are well differentiated, it is a benign (mature) teratoma. If less well differentiated, it is an immature (malignant) teratoma.

Neoplasia nomenclature - historic eponyms – “first described by…”
Malignant lymphoma (HL) of B Ly cell origin Hodgkin’s disease NHL – B Ly cell in children (jaw and GIT) Burkitt tumor Bone tumor Ewing tumor Kidney tumor - clear cell adenocarcinoma Grawitz tumor Malignant tumor derived from vascular epithelium (AIDS) Kaposi sarcoma Ovarian tumor derived from Brenner cells Brenner tumor Malignant chest wall tumor Askin tumor Skin tumor derived from Merkel cell Merkel tumor

. Hamartoma: a mass composed of cells native to the organ e.g. pulmonary hamartoma. Choristoma: a mass composed of normal cells in a wrong location e.g. pancreatic choristoma in liver or stomach. Malformation and not neoplasm.

Pulmonary Hamartoma

Pancreatic choristoma in gall bladder

Hamartoma and Choristoma
Neoplasia Hamartoma and Choristoma They are distinguished from neoplasms by the fact that they do not exhibit continued growth. they are group of tumor-like tissue masses which may be confused with neoplasms

Classification according to biological behavior
benign borderline malignant

Neoplasia Dysplasia : Definiton: a loss in the uniformity of the individual cells and a loss in their architectural orientation. Non-neoplastic Occurs mainly in the epithelia Dysplastic cells shows a degree of : pleomorphism, hyperchromasia,increased mitosis and loss of polarity.

Neoplasia Dysplasia does not mean cancer
Dyplasia does not necessarily progress to cancer Dysplasia may be reversible If dysplastic changes involve the entire thickness of the epithelium it is called : CARCINOMA IN-SITU

Neoplasia Carcinoma in-situ
Definition: an intraepithelial malignancy in which malignant cells involve the entire thickness of the epithelium without penetration of the basement membrane. Applicable only to epithelial neoplasms.

Dysplasia Features: Nuclear abnormality
Increased N/C ratio Irregular nuclear membrane Increased chromatin content Cytoplasmic abnormalities Increased rate of multiplication. Disordered maturation.

Dysplasia Uterine cervix
Sever Dysplasia Mild Dysplasia

Dysplasia (Papanicolaou test (pap smear)

Dysplasia Clinical significance:
It is a premalignant condition. The risk of invasive cancer varies with: grade of dysplasia (mild, moderate, sever) duration of dysplasia site of dysplasia

Dysplasia Differences between dysplasia and cancer.
lack of invasiveness. Reversibility

Carcinoma in situ A true neoplasm with all of the features of malignant neoplasm except invasiveness Displays the cytological features of malignancy without invasion of the basement membrane.

CHANGES IN UTERINE CERVIX

Squamous cell Carcinoma Uterine Cervix
Cervical SC carcinoma - infiltrating Dysplasia

Rate of neoplastic growth
How long does it take to produce a clinically overt tumor mass? original transformed cell ~1ng mass 30 doublings (2^30) yields 10^9 cells, 1 g 10 more doublings yields 10^12 cells, 1kg For more than ¾ total life span, tumor is not palpable How long does 30 to 40 doublings take? doubling time of tumor cells growth fraction of tumor cells rate at which tumor cells are shed or die

FIGURE 7-11 Schematic representation of tumor growth
FIGURE 7-11 Schematic representation of tumor growth. As the cell population expands, a progressively higher percentage of tumor cells leaves the replicative pool by reversion to G0, differentiation, and death. As tumors continue to grow, cells leave the proliferative pool in ever-increasing numbers as a result of shedding, lack of nutrients, necrosis, apoptosis, differentiation, and reversion to the nonproliferative phase of the cell cycle (G0). Thus, by the time a tumor is clinically detectable, most cells are not in the replicative pool. Even in some rapidly growing tumors, the growth fraction is only about 20% or less.

Tumor proliferation Proportion of cells in growth fraction declines as tumor grows High growth fraction tumors progress rapidly Leukemias, lymphomas, small-cell carcinoma Low growth fraction tumors progress slowly cell production 10% greater than loss Colon, breast adenocarcinoma Doubling time of clinically detectable colon or lung tumors averages about 2 to 3 months Causes infiltration, invasion, and destruction of the surrounding tissue

Metastasis Benign neoplasms do not metastasize
All malignant tumors can metastasize Except gliomas and basal cell carcinomas of the skin Metastatic spread strongly reduces the possibility of cure Overt metastases upon diagnosis in 30% cases, with occult metastases in 20% more

Pathways for metastases
Direct seeding of body cavities or surfaces Most frequently peritoneal cavity by ovarian cancer Lymphatic spread common for dissemination of carcinomas sarcomas may also use this route pattern of lymph node involvement follows the natural routes of lymphatic drainage biopsy of sentinel nodes is often used to assess metastasis Hematogenous spread typical of sarcomas but is also seen with carcinomas blood-borne cells follow the venous flow draining the site of the neoplasm liver and lungs are most frequently involved

Location preference Despite pathway of venous or lymphatic flow, some metastatic sites are frequently associated with some primary tumors: breast carcinoma spreads to bone bronchogenic carcinomas tend to involve the adrenals and the brain neuroblastomas spread to the liver and bones Despite the large percentage of blood flow, skeletal muscles and spleen are rarely the site of secondary deposits

Cancer incidence, risk US risk of cancer death 1 in 5
1.5 m new cancer cases and 0.5 m deaths from cancer in 2008 Cancers of the lung, female breast, prostate, and colon/rectum constitute more than 50% of cancer diagnoses and deaths

2008 statistics

Pakistan In Pakistan data from various cancer registries during showed that the most common types of cancer in males were lung, oral cavity, urinary bladder and larynx; while in female’s, breast, oral cavity and ovary cancers were the most common malignancies. Data from showed an increased incidence for lung, larynx and urinary bladder in males; and breast, oesophagus and cervix in females. Data from showed that breast and oropharyngeal cancers were the most common cancers (16.1% and 9.9% respectively) which have significantly higher incidence as compared to all other types of cancers

Epidemiology of cancer
Incidence varies with age, race, geographic factors, and genetic backgrounds Cancers are most common at the two extremes of age Geographic variation results mostly from different environmental exposures Most cancers are sporadic, but some are familial Hereditary predisposition may be autosomal dominant or autosomal recessive Dominant are usually linked to inheritance of a germ-line mutation of cancer suppressor genes Recessive are typically associated with inherited defects in DNA repair Familial cancers tend to be bilateral and arise earlier in life than sporadic cancers

. The mean age of the patients was 51 years in males and 50 years in females in data, which changed to 49 and 53 years respectively in data. The data from showed an overall drop in the mean age to 45 years for all patients.

Tobacco related cancers
Tobacco is the main independent risk factor for the development of cancer, especially those of the head and neck area and upper aero digestive tract. In Pakistan, about 50% tumors in males and 25% those of in females are associated with consumption of tobacco products. These include seven of the top ten cancers in males (lung, oral cavity, larynx, urinary bladder, pharynx, esophagus and prostate) and two of the top ten cancers in females (oral cavity and esophagus).

. Of all the cancer patients about 37.4% were users of Smokeless Tobacco (ST) while 23.6% were tobacco smokers. Over all oropharyngeal cancers have been shown to be the second most common malignancies throughout Pakistan and have significantly higher incidence as compared to other countries from WHO’s Eastern Mediterranean Region

. Majority of the patients (65%) at the time of diagnosis were in stage III or IV while about 40% were at stage I or II, with a small percentage with no histological confirmation. Data from showed that 53% were male patients. Pashtun represention was more (56%) followed by Baluchis and Punjabis

Molecular basis of cancer
Nonlethal genetic damage Tumors are monoclonal Four classes of normal regulatory genes are principal targets of genetic damage growth-promoting proto-oncogenes growth-inhibiting tumor suppressor genes genes that regulate programmed cell death (apoptosis) genes involved in DNA repair Carcinogenesis is a multistep process accumulation of multiple mutations required monoclonally initiated tumors evolve

Tumor progression FIGURE 7–24 Tumor progression and generation of heterogeneity. New subclones arise from the descendants of the original transformed cell by multiple mutations. With progression the tumor mass becomes enriched for variants that are more adept at evading host defenses and are likely to be more aggressive.

Figure 6-16 Flow chart depicting a simplified scheme of the molecular basis of cancer

Steps of normal proliferation
Growth factor binds to its specific receptor Transient, limited activation of the growth factor receptor with signal transduction Transmission of signal across the cytosol to nucleus via second messengers or signal transduction cascade Initiation of DNA transcription Entry and progression into the cell cycle

Proto-oncogenes, oncogenes
Proto-oncogenes: normal cellular genes whose products promote cell proliferation Oncogenes: mutant versions of proto-oncogenes that function autonomously without a requirement for normal growth-promoting signals Oncoproteins: proteins encoded by oncogenes

Cancer growth self sufficiency
Growth factors Autocrine loops Growth factor receptors Over-expression or always “on” Signal transduction proteins Intermediates in cascade, especially Gproteins, phosphorylases, kinases Transcription factors Cyclins and CDKs Uncontrolled cell cycle progression

Cyclin D–CDK4, cyclin D–CDK6, and cyclin E–CDK2 regulate the G1-to-S transition by phosphorylation of the RB protein (pRB). Cyclin A–CDK2 and cyclin A–CDK1 are active in the S phase. Cyclin B–CDK1 is essential for the G2-to-M transition. Two families of CDKIs can block activity of CDKs and progression through the cell cycle. The INK4 inhibitors (p16, p15, p18, and p19) act on cyclin D–CDK4 and cyclin D–CDK6. The others (p21, p27, and p57) can inhibit all CDKs.

Insensitivity to supressor signals
Classic example retinoblastoma gene Both copies of gene must be inactivated to block hold Familial predisposition due to one bad copy Sporadic cases arise from somatic mutations of both copies

RB Gene and Cell Cycle RB controlls G1-to-S transition of the cell cycle active RB (hypophosphorylated) binds to E2F preventing transcription of genes like cyclin E that are needed for DNA replication, resulting in G1 arrest Growth factor signaling leads to cyclin D expression, activation of the cyclin D-CDK4/6 complexes, inactivation of RB by phosphorylation, and thus release of E2F Loss of cell cycle control is fundamental to malignant transformation Almost all cancers will have disabled the G1 checkpoint, by mutation of either RB or genes that affect RB function, like cyclin D, CDK4, and CDKIs Many oncogenic DNA viruses, like HPV, encode proteins (e.g., E7) that bind to RB and render it nonfunctional.

The role of RB in regulating the G1-S checkpoint of the cell cycle
The role of RB in regulating the G1-S checkpoint of the cell cycle. Hypophosphorylated RB in complex with the E2F transcription factors binds to DNA, recruits chromatin remodeling factors (histone deacetylases and histone methyltransferases), and inhibits transcription of genes whose products are required for the S phase of the cell cycle. When RB is phosphorylated by the cyclin D-CDK4, cyclin D-CDK6, and cyclin E-CDK2 complexes, it releases E2F. The latter then activates transcription of S-phase genes. The phosphorylation of RB is inhibited by CDKIs, because they inactivate cyclin-CDK complexes. Virtually all cancer cells show dysregulation of the G1-S checkpoint as a result of mutation in one of four genes that regulate the phosphorylation of RB; these genes are RB, CDK4, cyclin D, and CDKN2A [p16]. EGF, epidermal growth factor; PDGF, platelet-derived growth factor

Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell cycle arrest in G1 and induction of DNA repair, by transcriptional up-regulation of the cyclin-dependent kinase inhibitor CDKN1A (p21) and the GADD45 genes. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53 triggers either apoptosis or senescence. In cells with loss or mutations of p53, DNA damage does not induce cell cycle arrest or DNA repair, and genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.

Tumor Host Interactions Clinical aspects of neoplasia
Local Effects Cancer Cachexia Paraneoplastic Syndromes Endocrinopathies Neuromyopathies Osteochondral Disorders Vascular Phenomena Fever Nephrotic Syndrome

Local Effects Tumor Impingement on nearby structures
Pituitary adenoma on normal gland, Pancreatic carcinoma on bile duct, Esophageal carcinoma on lumen Ulceration/bleeding Colon, Gastric, and Renal cell carcinomas

Local Effects Infection (often due to obstruction)
Pulmonary infections due to blocked bronchi (lung carcinoma), Urinary infections due to blocked ureters (cervical carcinoma) Rupture or Infarction Ovarian, Hepatocellular, and Adrenal cortical carcinomas; Melano-carcinoma metastases

Cancer Cachexia Progressive weakness, loss of appetite, anemia and profound weight loss (>20 lbs.) Often correlates with tumor size and extent of metastases Etiology includes a generalized increase in metabolism and central effects of tumor on hypothalamus Probably related to macrophage production of TNF-a and IL-1

Paraneoplastic Syndromes Endocrinopathies
Cushing’s Syndrome Adrenal carcinoma (cortisol) more common with benign adrenal processes. Small cell undifferentiated lung cancer (ACTH) released Inappropriate ADH syndrome (Hyponatremia) Small cell undifferentiated lung cancer (vassopressin-like hormone. Hypothalamic tumors (vasopressin)

Hypercalcemia (Cancer is the most common cause of hypercalcemia by either humoral or metastatic mechanisms) Squamous cell lung cancer (PTH-like peptide) Renal cell carcinoma (prostaglandins) Parathyroid carcinoma (PTH) Multiple myeloma and T-cell lymphoma (IL-1 and perhaps TGF-a) Breast carcinoma, usually by bone metastasis

Hypoglycemia - caused by tumor over-production of insulin or insulin like activities Fibrosarcoma, Cerebellar hemangioma, Hepatocarcinoma Carcinoid syndrome - Caused by serotonin, bradykinin or histamine produced by the tumor Bronchial carcinoids, Pancreatic carcinoma, Carcinoid tumors of the bowel

Polycythemia - caused by tumor production of erythropoietins Renal cell carcinoma, Cerebellar hemangioma, Hepatocarcinoma WDHA syndrome (watery diarrhea, hypokalemia, and achlorhydria) - caused by tumor production of vasoactive intestinal polypeptide (VIP). Islet cell tumors, Intestinal carcinoid tumors

Paraneoplastic Syndromes Neuromyopathies
Myasthenia - A block in neuromuscular transmission possibly caused by host antibodies against the tumor cells that cross react with neuronal cells or perhaps caused by toxins. Bronchogenic carcinoma, Breast cancer Carcinomatous Myopathy - probably immune-mediated

Paraneoplastic Syndromes Osteochondral Disorders
Hypertrophic Osteoarthropy - clubbing, periosteal new bone, and arthritis Isolated clubbing occurs in chronic obstructive pulmonary disease and in cyanotic congenital heart disease, but the full-blown syndrome is limited to lung cancer.

Paraneoplastic Syndromes Vascular Phenomena
Altered Coagulability - caused by the release of tumor products Migratory Venous Thromboses (Trousseau’s sign) Pancreatic, gastric, colon, and bronchogenic carcinomas; particularly adenocarcinoma of the lung. Marantic endocarditis - Small thrombotic vegetations on mitral or aortic valves that occur with advanced carcinomas.

Paraneoplastic Syndromes Fever
Associated with bacterial infections Common where blockage of drainage occurs Decreased immunity may play a role Not associated with infection Episodic as in Pel-Ebstein fever with Hodgkin’s lymphoma; poor prognostic sign in sarcomas, indicates dissemination Likely caused by response to necrotic tumor cells and/or immune response to necrotic tumor proteins.

Paraneoplastic Syndromes Nephrotic Syndrome
Excessive loss of protein in the urine probably caused by damage to renal glomeruli by tumor antigen-antibody complexes.

GRADING AND STAGING OF TUMORS
.

GRADING Degree of maturity or differentiation under the microscope
Histologic grade – resemblance between tumor and normal cells Nuclear grade – size and shape of nucleus, dividing cells

How is tumor grade determined?
Biopsy – benign or malignant - pathologist – level of differentiation

TUMOR GRADES Microscopic apperance of cancer cells
4 degrees of severity Grade: GX Grade cannot be assessed (Undetermined grade) G Well-differentiated (Low grade) G Moderately differentiated (Intermediate grade) G Poorly differentiated (High grade) G Undifferentiated (High grade)

GRADING SYSTEMS Different for different types of cancers
Gleason – prostate cancer Bloom-Richardson – breast cancer Fuhrman – kidney cancer

GRADING – TREATMENT For treatment and prognosis
Lower grade  better prognosis (outcome of diease) Higher grade  worse prognosis Important in treatment of  prim. brain tumors (astrocytomas) lymphomas breast cancer prostate

STAGING Extent of the prim. tumor and extent of spread in the body
Important - helps planning treatment - helps estimating prognosis - helps identifying clinical trials

STAGING SYSTEMS No unique staging system Common elements :
- Location of the primary tumor - Tumor size and number of tumors - Lymph node involvement (spread of cancer into lymph nodes) - Cell type and tumor grade (how closely the cancer cells resemble normal tissue) - Presence or absence of metastasis

TNM - system Most common Based on : T  extent of the tumor
N  extent of spread to the lymph nodes M  presence of metastasis Number  indicates size or extent of the prim. tumor and the extent of spread of metastasis

Regional Lymph Nodes (N)
Primary Tumor (T) TX Primary tumor cannot be evaluated T0 No evidence of primary tumor Tis Carcinoma in situ (has not spread) T1, T2, T3, T4 Size and/or extent of the primary tumor Regional Lymph Nodes (N) NX Regional lymph nodes cannot be evaluated N0 No regional lymph node involvement N1, N2, N3 Involvement of regional lymph nodes (number and/or extent of spread) Distant Metastasis (M) MX Distant metastasis cannot be evaluated M0 No distant metastasis M1 Distant metastasis (cancer has spread to distant parts of the body)

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