Winter semester Pathology I

1. Winter semesterPathology I Oncopathology: dignity, consequences of neoplasia, grading.... Lukáš Plank plank@jfmed.uniba.sk ÚPA JLF UK a MFN

2. DIGNITY (Biological properties/behavior of neoplasia): Principles of the tumour classification: histogenetical (typing) + dignity (biolog. property of the tumor disease) – - tumours are either benign or malignant. Basic terms: Tumor/parenchyma/stroma, differentiation/anaplasia Tumor: - stroma (support. tissue, vessels – blood supply), the stroma is critical to the growth, but doesn´t separate benign from malignant tumours. - parenchyma = clonal proliferation !!!

3. Differentiation versus anaplasia Differentiation:(diff. of parenchymal cells): = extent, to which they resemble their normal forebears (both morphologically and functionally) = diff. morphol., functional, antigenic, genetic, etc. – important for dg procedures (histochemistry, immunohistochemistry, molec. biol.). Anaplasia:lack of differentiation = hallmark of malignancy = „to form backward“ = loss of the structural/cytological/functional diff. (of normal cells), e.g.: stem cell --- different. cell --- specialized cells.

4. Differentiation versus anaplasia cont. Malignant tumours may show different degree of diff./anaplasia (but not benign – explanation ....) = insufficient differentiation or its loss (dedifferentiation) ?? – today: most cancers arise from neoplastic transformation of the stem cell, so failure of diff rather than dedifferentiation of specialized cells accounts for undifferentiated appearance.

5. DIGNITY D i g n i t y: Simple: tumours are either benign or malignant, but although they are most common, some more categories: benign, malignant, semimalignant, tumours of uncertain dignity (e.g. pheochromocytoma) The distinction benign versus malignant is made with remarkable accuracy based on clinical and anatomical (pathol.) criterias (only some neoplasias difficult to characterize - uncertain) Morphological criterias to use for dignity evaluation: growth patterns(macro and microscopical approach + histol. appearance

6. growth patterns: to study first by gross (then by histol.) appearance): a/ GROSS: all tumours grow by expansion, with gradual increas in bulk and resultant compression of the surrounding tissue, but: benign: merely oush aside the surr. norm. tissue and compressed adjacent stroma often forms a CAPSULE delineating the tumour – on surface: growth endophytic / exophytic The slow rate of growth of benign becomes significant, when compresses important adjacent stroma or when tumours is large enough to be unsightly. Various regressive changes: H, infarction, infection may cause a rapid increase in size of benign tu. But generally they grow slowly and often require years to attain a large size. This pattern in rate of growth is reflected also by Mi: mitosis are infrequent in benign. But other influences also play a role – hormonal (leiomyoma of the uterus: H-dependent, rapid enlargment in pregnancy, slow growth in menopausa). Benign: usually rounded, oval, encapsulated in majority – not always, but at least well circumscribed. The lack of capsule does not imply the malignancy – leiomyoma uteri – discretelly demarcated from the surr. smooth muscle by a zone of compressed myometrium, but no real capsule – practicum. Freely movable and often firm, uniform in gross app., unless regressive changes occur

7. Malignant tumour´s growth patterns (GROSS): Malignant tumours: grow also by expansion (first), but they infiltrate, invade and destroy the adjacent normal tissue = invasive ability = characteristicof malignancy – the outlines of malignant tumours are usually irregular and vague, rather than rounded and encapsulated as in benign tumours. Rarely encapsulated (local conditions, degree of diff. = rate of growth, etc). Gross (macro-)pathology: tend to have different colour, texture, consistency from the tissue of origin. Shape: irregular. poorly circumscribed, with projections of the maingrowth mass extending into adjacent tissue str. so as to make entire mass fixed = crab like (Latin for crab = cancer). Sarcomas – have a fleshy (fish-flesh-like) consistency, Ca are usually hard. However: regressive changes are frequent – ulceration etc alter the appearance of the tu. Terms to describe peculiar growth features: stenosing, infiltrating, diffuse, ulcerative, solid, cystic = description names for properties.

8. Tumour´s growth patterns - HISTOLOGY: • b/ HISTOLOGIC features of growth: • fibrous capsule separates the benign tumour from the host tissue, • malignant do not develope capsule and invade the tissue, • occasionally the tend to be encased by stroma of surr. tissue • – but always infiltration • = necessary to remove broad surgical margins !!! • – in your textbooks they call it local invasion. • vascular invasion (lymphatic channels, blood vessels /veins/, etc.) • neural/perineural invasion

9. Histol. (microscopic) appearance of the tumours: structure and cytohistology Benign (and many of the low grade tumours) : duplicate the structural patterns of the normal tissue so well, that they are unrecognizable as tumours (lipoma). Benign are composed of well diff. tissue (not only cells) that closely resemble their normal counterparts – the same is true for individual cells - lipoma – mature fat cells laden with cytopl. lipid. vacuoles, - chondroma – mature cartilage cells (synthesize cartilage matrix). Malignant: Such a close resemblance is true also for some better diff. malignant tumours. But the more malignant tumours, the more the individual cells deviate from the normal = ATYPIAS (although the changes seem to be only a MATTER of degree), they become sufficient to allow the cells to be recognized as cancerous.

10. Cytologic changes: cells as a whole, cytoplasm, nucleus, nucleolus Cells: larger than normal, irreg. outlines (bizzare forms), show pleomorphism (variations in size, shape from one to other), giant cells with multiple nuclei, unusual shapes are frequent in high grade malig (polymorphia, difficult to identify the cells origin) Nuclei: deviations from the normal (identical to normal = benign + low grade), in cancer: enlargement, PM of nuclei = anisonucleosis (diff. in size and shape and chromatin structure), alteration of N : Cytoplasm ration (cytology !!!). Chromatin is condensed or increased (more DNA), nucleoli prominent, nuclei lobated or otherwise irregular – Chromosome analysis: PLOIDITY (aneuplody, polyploidy, hyperploidy),

11. Cytologic changes + functional properties, etc ALL these features characterize what is called: ATYPICAL CELLS – criterias of malignancy. Others parameters: well diff.: cytoplasm contains the characteristic constituents, secretion and/or products (cross striations, secretions as mucus, keratin). Enzymes formed by normal cells may be found in better diff. Ca and their presence may assist in proper classif. of tu. With increasing anaplasia, the tumour loses such refinements. E.g. : it is unusual for cancer cells from bronchial epith. to show cillia. Ag – immuno Genes – molec. biol. (promotors, supressor etc.)

12. Consequences of the tumour disease (not only tu, but tu dis.): LOCAL INFLUENCES versus DISTANT /GENERALIZED: LOCAL: infiltration, invasion, destructiveness, angioinvasivity (infiltration/invasion of to vessels), local pressure on vessels – circulat. disturbances (venostasis, necrosis – CNS), local destruction: ulceration, fistulation (e.g. vesico-rectal), perforation (into the perit. cavity – bleeding, peritonitis), penetration (into adjacent tissueúorgan – Ca ventriculi into pancreas), necrosis in situ, exophytic growth and occlusion of the lumen – intest. Ca – ileus infiltration of the nerves – neurologic disturbances, pain

13. Consequences of the tumour disease (not only tu, but tu dis.) - DISTANT: the invasive property of cancer – not only local extension, but also promotes MTS (definition = developm. of second. implants – MTS discontinuous with the primary Tu) – to distinguish from local extension !!! - common mistake of students. MTS: a process in which malign tu cell invade vessel / local tissue space in such manner, that they may detach and migrate/or to be transported/transplanted to a distant place, where they lodge and grow in a new location to form secondary tu mass. The ability to metastasize = property of many (not all) malignant TU, but not of any benign tumour. Explain: semimalignant + problems of recent clasifficational approaches: low risk, medium and high risk (soft tissue tu, neuroendokr. /carcinoids/, etc.

14. Consequences of the tumour disease (not only tu, but tu dis.) - DISTANT: Generalisation The usual routes of MTS dissemination – explain GENERALISATION: through Ly vessels, blood vessels (as thrombi), through serous cavities, occasionally by transport in the cerebrospinal fluid (liquor), or through hollow structures and rarelly by contact with an aposing structures. Most common route: for MTS spread of Ca: lymphatic vessels – LN Sarcomas favor the venous route. DETAILS - textbooks

15. Effect of the tumour on the host – consequences cont. Tu (neoplast. dis) – host interplay ´s factors inherent in the Tu + others in the host. All factors combine to determine the ultimate biological behaviour of the neoplasm = BIOLOGICAL/ CLINICAL criterias of the dignity. Usual course of untreated malignant tu is continual growth + MTS extension with systemic effects t- to weaken the host in the diverse ways. Treated – the course is influenced by Therapy. Dg /biopsy – treatment (0 disease = remission : CR, PR, latent disease, active disease, MRD) Remission: morphol., phenotypic, molecular. Reccurrence: clinical term used to describe the appearance of the Tu following its apparent removal/destruction. Indicates: some of the Tu cells have survived and event. multiplied to such extent that Tu is again clinically obvious. (In hematology = relaps). Sometimes late reccureences – dormant tu cells over years. Survival at 5/10 years level = efficiency of the Th

16. Consequences global: a/Cachexy: malignant atrophy – extreme wasting of the whole body in 50-80% of all oncological patients – represents a bad prognostic factor. Etiology not completelly known and is multifactorial. It is necessary to distinguish primary and secondary cachexia: secondary C. – functional or anatomic alterations of GIT (e.g.. partial obstruction of GIT) or in therapy affecting GIT = postoperative ileus, colitis, emesis induced by therapy, anorrhexy (CHT has negative influence, the same is true for RadioTh), reduced food intake, anxiety primary:hormonal and metabolic abnormalities, they include increased glucose-production, incr. proteocatabolism, incr. lipolysis, oxidation of fat acids, insulin resistence, katabolic hormonal changes, etc. The most important role is made by cytokines – TNF, IL-1, interferon gamma and D-factor, may be influenced by repeated infections, necrosis – release of toxins,

17. Consequences global: Cachexy is different by diff. tumours – some thought that the tu as a parasite, but it is not primarily due to extra high demands of widespread tu, nor is due to any specific toxins. Similar cachexia in patients dying of other wasting dis (diss. TB. AIDS) Consequences of the cachexy: muscle weakness, decreased resistence to infections (respiratory, urinary), decubites, thromboses, slow wound healing, tired, global psychical and physical weakness. It is important to recognize this state before the exhaustion of the organism, when still some deposits are preserved.

18. Consequences global: b/ fever– mostly due to second. infections by ID, TNF (destruction of cells) c/ anaemia– decreased life-time of Ery , occult haemorrhage, + massive MTS to the BM d/ depression of the immunity: – decreased nourishment = hypoproteinemia = hypogamaglobulinemia + LN MTS= decre. cellular immunity = opportunistic infections (candida, HSV) + iatrogenic (Cytostatic Th, corticosteroids) e/ production of hormones: in tu arising from endocrine glands or not (ben or malign, especially well differentiated may or may not produce effective H, the production is unregulated – symptoms of excessive h-production (hyperinsulinism, acromegaly, hyperparathyreoidism, etc.)

19. Consequences global: f/ paraneoplastic syndromes: other than cachexia – in patients with cancer – can´t be explained by spread: IMPORTANCE ! – first/early manifestation of Tu: acanthosis nigricans – skin change Ca stomach, peripheral neuritis, disorders of CNS (brain atrophy) – Lung Ca, Dermatomyositis – various Ca types, Increased blood coagulability – venous thrombosis – Lun/pancreas Ca, Endocarditis (non-bacterial) – advanced Ca Herpes zoster – Ca colonis g/ others: changes of the blood picture: leucocytosis, cytopenia, anaemia, pancytopenia, connective tissue disease, endocrinopathies - hypoglycemia, hypercalcemia..