Doubling time Important for tumor growth 10milimicron diameter Ca cells require 20 doublings Short interval between mitoses---rapid increase in size Doubling times are inconstant even in same tumor Rate of growth Benign tm grows slowly over a period of time Most cancers grow rapidly Broad range of growth rate Rate of growth maynot be constant over time Hormones, blood supply,unknown influences Growth rate correlates with level of differentiation Growth rate Microscopic clue for growth rate is mitoses Malignant tumor 20 or more mitoses per 1000 cells Benign or normal tiisue less than 1 mitoses per 1000 cells Ionizing radiotherapy/chemotherapy--suppression of mitoses in tumor cells---cancer therapy Kinetics of tumor cell growth The rate of growth depends upon growth fraction Degree of imbalance between cell production and cell loss Leukemias and lymphomas, certain lung Ca show rapid clinical course---high growth fraction Growth fraction has effect on their susceptibility to cancer therapy Anticancer drugs act on cells that are actively synthesizing DNA Frequency of mitoses is a crude reflection of growth rate Local growth and invasion All tumors grow by expansion with a progreesive increase in bulk--compression of surrounding tissue Benign tumors ---push aside the normal tissue---pressure atrophy of normal tissue—forms a capsule---deliniates the tumor Local growth and invasion Malignant tumors---invade, infiltrate and destroy the adjacent normal tissue Outlines are irregular Not rounded and encapsulated Some slowly expanding malignant tm---may develop fibrous capsule---tiny crablike feet can be seen microscopically---infiltration, Not a real capsule---pseudocapsule Insitu carcinoma Preinvasive stage Cytologic features of malignancy Without invasion of Basement membrane Extent of infiltration in invasive Ca---practical importance in therapy Inadequate excision---reccurrence is inevitable Local growth and invasion Most cancers---are obviously invasive Penetrates the wall of uterus or GIT Fungate through the skin surface Permeate lymphatics, blood vessels and perineurial spaces Next to development op metastases invasiveness is the most reliable feature that differentiates malignancy from benign tumors Invasion Ca cells elaborate products that directly or indirectly influences invasion Proteolytic enzymes Lytic factors Collagenolytic factors---squamous cell Ca Osteoclast-stimulating factors---bone erosion---Multiple myeloma, bone metastases Invasion Attachment of tumor cells to matrix components (laminin-fibronectin) Secretion of proteolytic enzymes that locally degrade the matrix components Migration of the tumor cells into the degraded zone of ECM Malignant cells are far less cohesive than normal cells ( migration is easy) Tissue vulnerability for invasion Elastin fibers are much more resistant as compared to collagen fibers Densely compacted collagen ( membranes, tendons, joint capsules) resist invasion for long periods Cartilage is the most resistant Cartilage resistancy for tumor invasion Physiochemical characteristics of the matrix Biological stability and slow turnover of cartilage Elaboration of inhibitory substances Antiangiogenesis factor Inhibitors of enzymes involved in the growth and invasiveness of Ca cells Local invasion Arteries are much more resistant than veins and lymhphatics Elastin content of arterial walls Elaboration of proteases inhibitors Soft tissues and muscles are easily invaded Benign tumorsXMalignant tumors Well dif. Structure is typical of tissue of origin Progressive and slow growth rate Mitotic figures rare and normal Cohesive expansile mass, well demarcated margins No metastases Some lack of dif. anaplasia, struc. Atypical Erratic growth rate, slow to rapid Mitotic figures numerous and abnormal Locally invasive, infiltrating normal tissue Metastases frequently Metastases Tumor implants discontinuous with the primary tumor Feature of malignancy Malignant Tm cells invade vessels/tissue spaces—they migrate or transported to distant site---they lodge and grow in the new location---secondary tumor masses Metastases Few exception---all Ca can metastasize Glial brain tumors, basal cell Ca of skin More aggressive More rapidly growing Larger primary Tm Increased risk of metastases Routes for metastases Direct seeding of body cavities or surfaces Lymphatic spread Hematogenous spread Seeding of body cavities and surfaces Malignant cells penetrate into a natural open field Peritoneal, pleural, pericardial spaces Subarachnoidal cavity Joint spaces Superficial seeding, without penetrating into the tissue Mucus secreting ovarian and appendicial Ca fill the peritonel cavity---gelatinous masses--pseudomyxoma peritonei Lymphatic spread The most common route for the metastatic spread of cancer Tm cells have invaded lymphatic vessels--they may detached to become emboli--or they may form a continuous growth (Lymphatic permeation) Local spread of disease Emboli formation is more common Lymphatic spread Emboli formation---regional lymph nodes--multiplication of tumor cells---İnvasion of lymphoid pulp---develop supporting stroma Follows the natural route of drainage Regional nodes serve as a barrier for a time Tm cells after arrest within the node maybe destroyed Skip metastases Venous/lymphatic anastomoses Inflammation Radiation Obliterated channels Enlargement of lymph nodes in cancer Spread and growth of Ca cells Follicular hyperplasia ( reactive ) Proliferation of paracortical T cells and sinus histiocytes Regional lymph nodes Carcinoma of breast---axillary lymph nodes Carcinoma of scrotum---Inguinal lymph nodes Carcinoma of stomach---grater and lesser curvature lymph nodes Carcinoma of larynx---cervical lymph nodes Carcinoma of prostate---iliac and paraortic nodes Hematogenous spread Typical route for sarcoma But frequently carcinomas also metastasize this way Venous invasion---blood borne cells follow the venous flow draining the site of neoplasm The liver and lung are most common sites Portal area---liver, Caval system---lungs Vascular size,permeability,local nourishment Hematogenous spread Cancer arising in close proximity of vertebral column---embolize through the paravertebral plexus Vertebral body metastases Thyroid Ca, prostate Ca Unusual sites---retrograde metastases--venous obstruction or abnormal anastamoses Doğumsal tümör Pathologic fracture Soft tissue tumor Metastatic dissemination Small undifferentiated tm cells with muscle differentiation Eosinophilic cytoplasm Like striated muscle Metastastic breast carcinoma at bone Other possible routes Through spinal fluid Through ureters Through bronchi Through apposing tissues Ca may be mechanically transported and implanted by a surgeon scalpel, needle or sutures Metastasis is less invasive than primary tumor Tends to be more regular in shape and outline Sometimes even encapsulated If there are multiple tumoral nodules in an organ---probably metastatic If multiple metastasis present local therapy will not cure the disease Steps in metastases Invasion of tumor cells into vessels or appropriate tissue spaces Detachment of the cells with embolization or other mechanical transport Lodgement and progressive growth of the cells in a new location Metastases Metastatic abilty of tumor is influenced by its location Nature of the vascular supply The Tm cells in the blood stream does not necessarily mean that metastasis take place Many tumor cells maybe lost along course All organs or tissues are not equally susceptible to the development of metastases Relatively uncommon in spleen and skeletal muscle Metastatic cascade Tumor cells must penetrate the extracellular matrix at several stages Firs barrier---basement membrane Highly specialized sheet of ECM Interstitial matrix Vascular basement membrane Metastatic cell must have the ability to attach, to degrade and penetrate the ECM Sürrenalde metastatik akciğer karsinomu Lymphoma Liver involvement Cerebellar astrocytoma References and further reading Robbins Pathologic Basis of Disease, Cotran, Kumar 2004 Pathology Illustrated, Macfarlane, Reid,Callande 2000 Sandritters Color Atlas and Textbook of Macropathology, Thomas, Kirstn, 1984 Basic Pathology, 6th ed, Kumar, Kotran, Robbins Pathology Rubin, Farber, 1999 Mohan Harsh Textbook of Pathology, 2005 Cerrahpaşa Pathology archieves Internet (various medical web sites)
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