Neoplasia Characteristics of benign and malignant neoplasms Differentiation and anaplasia + nuclear and cellular pleiomorphism = hyperchromatism = muclear-cytoplasmic ratio = mitoses + tumour giant cells Rate of growth Local invasion Metastasis + spread into body cavities = invasion of lymphatics = haematogenous spread MAKE UP A TABLE OF COMMON TUMOURS, Epidemiology Geographic and environmental factors Age Heredity Acquired preneoplastic disorders Molecular basis of cancer Oncogenes, Protooncogenes Protein products of oncogenes > growth factors - growth factor receptors + signal-transducing proteins = nuclear transcription proteins - cyclins and eyelin-dependant kinases Activation of oncogenes = point mutations = chromosomal rearrangements = _ gene amplification Cancer-suppressor genes + protein products of tumour-suppressor genes = Rbgene = ps3 = BRCA-1 and BRCA-2 = APC gene - MF-I gene = Call surface receptors - WIl Genes that regulate apoptosis, Genes that regulate DNA repair Molecular basis of multistep carcinogenesisMAKE UP A TABLE OF ONCOGENES MAKE UP A TABLE OF TUMOUR-SUPPRESSOR GENES Biology of tumour growth Kinetics of tumour cell growth doubling time growth fraction Cell production and loss ‘Tumour angiogenesis ‘Tumour progression and heterogeneity Mechanisms of invasion and metastasis invasion of extracellular matrix detachment of tumour cells from each other ~ attachment to matrix components - degradation of extracellular matrix - migration of tumour cells vascular dissemination and homing of tumour cells Chemical carcinogenesis Initiation Promotion Radiation carcinogenesis UV rays Ionizing radiation Viral and microbial carcinogenesis DNA viruses HPV. EBY HBV RNA oncogenie viruses Helicobacter pylori MAKE UP A LIST OF CARCINOGENS Host defense against tumours Tumour antigens ‘Tumour-specific shared antigens Differentiation antigens Antigens resulting from mutations Over-expressed antigens Viral antigens Tumour assosciated antigens ImmunosurveillanceClinical features of tumours Local and hormonal effects Related to location Hormone produetion Cancer cachexia Paraneoplastic syndromes Endocrinopathies Hypercaloemia Acanthosis nigricans Finger clubbing and hypertrophic arthropathy ‘Thrombotic diatheses Laboratory diagnosis of cancer Histologic and cytologic methods Fine needle aspiration Cytologic smears Immunohistochemistry DNA probe analysis Flow cytometry Tumour markers DEVELOP A CANCER TABLE WITH CELL TYPES, CAUSES, TREATMENTS AND HISTOLOGYRACS - ONCOLOGY - MCQ JOHN BLENNERHASSETT DUNEDIN, QUESTIONS 1-5 CHOOSE THE SINGLE BEST OPTION 1. The closest association between development of malignancy and radiation is seen with: A. thyroid B. salivary gland é, bone D. leukaemia E. breast Ans: D Robbins Sth Ed, Ch 7, p 285. ‘This question does not highlight that CML does not share the likelihood to result from radiation that is seen with other leukaemias. Likewise, thyroid cancer following radiation to head and neck is a major risk only following radiation in childhood. The story of bone cancer that followed the swallowing of repeated small doses of radium in young women who painted the watch dials (they "pointed" their brushes by moistening them with their tongues!) is famous. However, this hierachy (leukaemia > thyroid > breast, lungs, salivary gland > skin, bone, G-I tract) would parallel experience following the use of shoe-store X-ray fluoroscopes in the 1950's, Hiroshima, ‘Nagasaki and the Marshall Isiands and the post-Chernobyl epedemics, as well as the incidence of papillary cancer of the thyroid following chidhood radiation of tonsils or thymus commonly done for trivial problems in the 1950's. 2. In the following sequential developments in the "metastatic cascade", the SECOND of the events t0 occur is: degradation of collagen and other matrix components tumour embolisation extravasation carcinogenic cell transformation tumour cell interaction with platelets Robbins Sth Ed, Ch 7, p 276-27! ‘The "metastatic cascade" concept is a useful one, in that it takes the whole process and itemises the steps in sequence from cancer cell “initiation” through the concepts of genetic instability, selection of "metastatic subclones", the necessity for acgisition of new characteristics of cells to break down extracellular matrix and so on. Detailed consideration of each of these areas is considered in preceding or following sections of the same chapter. 3. Each of the following is true of carcinogenic initiation, EXCEPT: effects are rapid effects are reversible induces DNA alteration has "memory" can be active when given in divided doses Ans: B_ Robbins Sth Ed, Ch 7, p 281-283. This section deals with the processes of initiation and promotion of oncogenesis. It appears under the section on chemical carcinogenesis but is applicable, with appropriate modification, to radiation and viral oncogenesis. The delineation of agents rigidly into the classes of "complete" carcinogens (oncogens, if you like, but not oncogenes), initiators and promoters is conceptually useful, but not always easy. However, the concept that initiators damage DNA in a fashion which is not susceptible to repair (either widely, or in a particular group of individuals with genetic defect in DNA repair capability) is central to our understanding of oncogenesis. Promoters then apparently "push" the cell that extra step(s) to uncontrolled growth. moaw> 4. In the following steps in the "metastatic cascade", the SECOND occurrence is: development of a "metastatic subclone" extravasation clonal expansion, growth and diversification passage through extracellular matrix tumour cell embolus mo m>Lonct y MCO / MAY "95 / BE Ans: A Robbins Sth Ed, Ch 7, p 276-279. See question 2 for the start of discussion of this question. This particular question is based on the concept that, before cancer cells can invade (or metastasise), there has to bet (1) initiation, (2) promotion, (3) proliferation (clonal expansion, growth) and diversification through subclone selection which results from the inherent geneti¢ instability of cancer cells, (4) selection of a "metastatic subclone" (which will require stich diverse abilities as laminin and fibronectin reception capability, elaboration of ECM proteases etc., locomotion capability, chemotaxis (??)), before any of the possible responses (D), (E) or (B) come onto the scene (these last three are in order of events also). 5. The best su een with: al with thyroid neoplasia is A. sporadic (non-familial) medullary carcinoma B. — giantcell carcinoma C. follicular carcinoma D. papillary carcinoma E. small cell carcinoma Ans: D Robbins Sth Ed, Ch 25, p 1138. Itis worth knowing that papillary cancer of the thyroid has a very good medium and even long term outlook, even in the presence of disseminated disease, Familial medullary cancer also has aan excellent prognosis; this is not shared by the sporadic (non-familial) form of medullary cancer, which also has marked differences in clinical presentation. Follicular cancer has an outlook somewhere between papillary/familial medullary and the highly malignant giant and small cell (collectively “undifferentiated") forms. QUESTIONS 6-11, CHOOSE =A: ‘1,2 and3 B: land3 9 C: 2Qand4 D: 4’only E: ALL 6. The human papilloma virus (HPV) has been causally implicated in the genesis of: 1. nasopharyngeal cancer 2: the uterine cervix 3. Hodgki 4. 's disease, nodular sclerosing type skin cancer in individuals with inherited or induced (renal transplant) cell-mediated immune defects Ans: C (2, 4 correct) Robbins Sth Ed, Ch 7, p 286-287, Ch 23, p 1048, This question highlights the close association of HPV (especially types 16, 18 and 31) with anogenital cancers (especially cervix). HPV (multiple strains) is known as the cause of venereally transmitted vulvar condyloma acuminatum. High risk HPV strains (16,18 and 31): (1) often become incorporated in the host genome, (2) cooperate in cultured cells with the ras oncogene to form tumourigenic foci, and (3) the probable transforming sequences of HPV are consistently found in squamous cancer cells from clinical cases of CIN and invasive cancer. Defective CMT (hereditary, renal transplant immunosuppression), HPV (5, 8, 14) and sunlight appear to interplay in formation of skin cancer 7. _Inrelation to the suggested causal role of Epstein-Barr virus (EBV) in African Burkitt's lymphoma, which of the following statement(s) is/are true ?: 1. Burkitt's lymphoma patients have elevated titres against EBV capsid antigen 2. _ EBV capsid antibody titres correlate with risk of developing the tumour 3. _ EBV has strong tropism for human B lymphocytes 4. EBV infection is restricted to the geographic locales where Burkitt's lymphoma is endemic Ans: A (1, 2, 3 correct) Robbins Sth Ed, Ch 7, p 287-289, This question relates to African Burkitt;s lymphoma, AI patients test as in response (1) and response (2) is also valid. Response (3) is valid universally, However EBV infection is global (response (4) is incorrect); other factors are clearly involved in the genesis of Burkitt's lymphoma. Normal individuals infected with EBV are asymptomatic or develop infectious mononucleosis; ? is ‘malaria-induced immuno-incompetence co-oncogenic. Both EBV and sporadic Burkitt'sRACS | ONCOLOGY MCO / MAY "95 / JB lymphoma have a chromosomal (8:14) translocation (this apparently influences activation of an oncogene [e-myc]). Nasopharyngeal cancer has 100% concordance with the presence of EBV in the cancer genome (and a similar geographic restriction in incidence). 8. Cushing's syndrome may be caused by neoplasms originating in the: 1. bronchus 2. pituitary 3. pancreas 4. breast Ans A (1, 2, & 3 correct) Robbins Sth Ed, Ch 7, p 296. Responses | and 2 are straightforward (pituitary as a "normal" producer; bronchus as an “inappropriate” producer). By the rules for this type of MCQ, response 3 must be correct, and is ! Responses are referenced in table 7-9. 9. The following clinical cancers exhibit "site selection" for metastatic growth, which appears to be not specifically related to anatomical drainage of the primary site: 1. testicular teratoma 2. neuroblastoma 3. rhabdomyosarcoma 4 bronchial carcinoma Ans: C (2, 4 correct) Robbins Sth Ed, Ch 7, p 279. This is a repeated and well-documented observation for cancers 2 and 4. It has very strong experimental support as a concept (ie. "homing" of metastases of certain cancers to particular tissues, even when in ectopic sites). Clearly, the concept of endothelial/tumour cell ligand/receptor interaction is an attractive one, but the actual chemical reaction(s) involved is as uncertain now as the reason for granulocyte "pavementing” was a decade ago! 10. The Philadelphia (Phi) chromosome can be identified in chronic myelogenous leukaemia (CML) in the following cell lines: 1. myeloblastic 2 lymphoid 3. megakaryocytic 4. monocytic Ans: B (1, 3 correct) Robbins Sth Ed, Ch 14, p 655. The important point here is the evidence that "..most types of human cancer have chromosomal abnormalities .... in many types of cancer, the defects are consistent... there is a strong possibility that gene changes are present in all." The particulars for the Phi chromosome are conceptually immaterial except insofar as they tell us something of the common lineage of myeloblastic, erythroblastic and megakaryocytic lines. Type C- if 1 is correct, 3 must be ! 11. Medullary carcinoma of the thyroid may cause: 1 myasthenic syndrome 2. diarrhoea 3. hypocalcaemia 4. Cushing's syndrome Ans: C (2, 4 correct) Robbins Sth Ed, Ch 25, p 1140-1141. ‘This is one of the versatile neuroendocrine carcinomas which can secrete serotonin, ACTH or, less often, a number of the more obscure hormonally active materials. Myasthenic syndrome (bronchial cancer, thymoma) and PTH/TNF-a (bronchial and other cancers) are not in the repertoire. Hormonal activity with this particular thyroid cancer may be seen in patients either with or Without familial association. If 2 is correct (commonest symptom), 4 must be right also ! The six questions portrayed in the coded Type "C" mode contained responses which are perhaps only fair if some of the responses can be reached from the code - ie. rather obscure or difficult for simple "True/False" without guiQUESTIONS 12-36. For each response answer: T if the response is true F if the response is false 12. Using the standard accepted model of the cell growth cycle, the theoretical growth of a cancer clone (30 doublings = | x 10° cells = 1 gram) is never achieved because cells are lost to the proliferative pool when they: 1. enter the Go phase 2. are in the Grphase 3. enter the Gz phase 4. differentiate Ans: (T, F, F, T) Robbins 5th Ed, Ch 7,p 272-274. ‘The "30 doublings = 10° cells = 1 gram; 10 more doublings = 10!2= 1 kg = maximum possible tumour burden" concept is alive and well! This question accepts that model, asking for the reason(s) why itis not applicable to clinical cancer. Cells in any of the G,, S, G; or M phases of the cell cycle are considered to be in the "proliferative pool” by definition; in clinical cancer cells are lost to the proliferative pool for a number of reasons and cell proliferation is not synchronous. Much of theoretical oncology deals with "models" - ty "Gompertzian growth curve"! 13. ‘There is a positive correlation, experimentally and/or clinically, between metastatic potential of cancer cells and their: 1. elaboration of plasminogen activator 2. blockade of fibronectin receptors on tumour cells 3. secretion of type IV collagenase 4. density of laminin receptors Ans: (T, F, T, T) Robbins Sth Ed, Ch 7, p 276-278. Responses 2 and 4 (p 259) relate to the apparent importance of capacity of tumour cells to bind to collagen of basement membrane (type IV - laminin) and interstitium (type I - fibronectin); 1 and 3 refer to the importance of breakdown of intercellular matrix, which creates space for cancer cell invasion and probably also provides growth and chemotactic stimuli (for stromal and ? also cancer cells). Experimental fibronectin receptor blockade (using an analogue which occupies the receptor sites for laminin on tumour cells) inhibits formation of lung metastases. 14, Extracellular matrix degradation by tumour cells and the products of matrix breakdown result in production of: 1. angiogenesis factors 2. chemotaxis factors 3. growth factors 4. aphysical passage for tumour cell migration Ans: (I, T, T, T) Robbins Sth Ed, Ch 7, p 278-279. See question 13 for discussion relevant to this question. 15. Laminin in basement membranes has binding sites for: 1. macrophage Fe receptors 2. epithelial cell membrane receptors 3. proteoglycan 4. collagen type IV Ans: (F, T, T, T) Robbins Sth Ed, Ch 2, p 42. See question 13 for discussion. Laminin is not a ligand for Fe receptors. 16.* In experimental studies, when compared with normal cells, cancer cells show: 1 reduced intercellular cohesiveness 2. resistance to the actions of cytokine growth factors 3. “immortality” in tissue culture 4. requirement of a solid surface for growth ("anchorage dependence") Ans: (T, F, T, F) Robbins 4th Ed, Ch, p 254-255. Interestingly, this important information is not itemised Robbins 5th’ Ed and therefore cannot be asked.RAI Lape 17, When complicated by widespread metastatic tumour involvement, the following cancers characteristically cause hypercalcaemia: 1. kidney 2. lung 3. breast 4. prostate Ans: (I, T, T, F) Robbins Sth Ed, Ch 7, p 296. (Table 7-9). Hypercalcaemia is probably the commonest paraneoplastic syndrome. In some cancers, this is, simply the calcaemic effect of rapid bone destruction; in others the elaboration of a calcaemic tumour secretion (PTH-like; TNF-a) is either known or assumed to cause the raised plasma calcium. With tumours 1, 2 and 3 , both mechanisms are thought often to be active. 18. Choriocarcinoma of gestational origi 1. if untreated, parallels the behaviour of primary ovarian choriocarcinoma 2. metastases early and widely 3. has. generally good prognosis with chemotherapy 4, can be monitored clinically by plasma gonadotrophin (HCG) levels 'T, T, T, T) Robbins Sth Ed, Ch 23, p 1085-1086. This cancer is one of the success stories of modern systemic chemotherapy. It contrasts markedly with the still formidable mortality of non-gestational choriocarcinoma, despite the fact that both neoplasms share the same morphology, cell markers, HCG elaboration etc. 19. Neuroblastoma of the adrenal: 1. commonly matures spontaneously to form a ganglioneuroma 2. isa cancer of childhood 3. commonly causes hypertension 4. has often metastasised by the time of diagnosis Ans: (F, T, F, T) Robbins Sth Ed, Ch 10, p 459-461. Neuroblastoma has been documented to mature to ganglioneuroma - to find out why is currently akin to the quest for the holy grail! This type of regression/maturation is rare. More than 90% of adrenal neuroblastomas secrete catecholamines, but hypertension is rare. 20. — Carcinoma of the bronchus may cause: 1. hypocalcaemic syndrome of pseudohypoparathyroidism 2 Cushing's syndrome 3. hyponatraemia 4, inappropriate secretion of norepinephrine Ans: (F, T, T, F) Robbins Sth Ed, Ch 7, p 296. (Table 7-9). Tam unaware of the occurrence of either syndrome 1 or 4 in neoplasia as a “paraneoplastic syndrome (epinephrine secretion in phaeochromocytoma, for instance, is predictable). Options 2 and 3 are common in lung cancer. 21. Carcinoid tumours 1. are most commonly found incidentally at surgery or autopsy 2. show neuroendocrine differentiation 3 are clinically innocuous neoplasms 4, most commonly grow "within the range of the competent sigmoidoscopist" Ans: (T, T, F, F) Robbins 5th Ed, Ch 17, p 819-820. Options 1 & 2 are clearly correct. However, despite the truth of option 1, carcinoids presenting with symptoms referable to the presence of the tumour (either its mass effect or due to its secretory products) present a formidable problem thereafter. Obstructing gut carcinoids usually eventually metastasise and bronchial carcinoids are "..often locally invasive or occasionally capable of metastasis". Option 4 is wildly optimistic, even for exhibitionists!L BE 22. In human cancers, recent research suggests that cancer cells, when compared with normal tissues derived from labile cell populations: 1. have a higher percentage of terminally maturing cells, 2. donot have a shorter cell cycle time 3. have a greater proportion of their cells in the replication cycle (growth fraction) 4. replicate at a rate in excess of most labile cell populations Ans: (F, T, F, F) Robbins Sth Ed, Ch 7 p 273-274, This is a difficult concept - at least as discussed in any treatise on neoplasia with which I am familiar. The points are valid - responses 1, 3 and 4 are false and 2 is correct - the explanations for continued growth are, however, not explored in depth and the bland statement " . there is an imbalance between cell production and cell loss..." is meant to explain it all! Perhaps a major factor here is that in normal epithelia (for example), mitosing cells are present only in the basal layer (skin or gut crypt) and the bulk of the epithelial cells are terminally maturing, In CIN, for example, mitoses are present at all layers of the dysplastic epithelium - I suspect that the cells being included for defining the "proliferative pool" stacks the result. Perhaps more importantly, labile cells such as granulocytes and gut epithelia have a very short life span - cancer cells may well be more robust -I am sure that there are good studies on this subject. 23. Colonic carcinoma has an increased incidence in individuals with 1. hyperplastic polyps 2. Peutz-Jegher's syndrome 3, tubular adenomas 4. chronic ulcerative colitis Ans: (F, F, T, T) Robbins Sth Ed, Ch 17, p 809 & 815. Chronic ulcerative colitis is the most significant non-neoplastic precursor of carcinoma and the debate over whether or not adenomas (tubular or villous) are precancerous has long been settled! Hyperplastic polyps have no premalignant potential, but may be admixed with adenoma whereupon the lesion takes on the premalignant mantle of the adenoma, Peutz-Jegher’s polyps are considered to be hamartomas with no premalignant potential in themselves. The syndrome is, however, associated with an increased incidence of cancers of other sites. 24. Malignant melanoma: 1. is usually uniformly black or amelanotic 2. may arise in diverse mucosal sites 3. usually has irregular "notched" borders 4. prognosis is predicted most accurately by the mitotic rate Ans: (F, T, T, F) Robbins Sth Ed, Ch 26, p 1179-1181. The points highlighted here are that malignant melanoma is characterised by irregularity of colour within individual lesions and usually an irregular outline. ‘There are many factors being investigated as to relevance in terms of prognosis; the "...nature and extent of the vertical growth phase, however, determines the biologic behaviour..." Melanomas occur in a variety Of sites other than skin (including virtually every mucosa). 25. — Dysplastic naevi 1. very seldom occur on other than sun-exposed skin 2. usually have pale edges with a uniform central "salmon pink" papule » most will develop into malignant melanoma within two decades if not ablated 4. show melanocytic atypia and superficial dermal lymphocytic infiltrate Ans: (F, F, F, T) Robbins Sth Ed, Ch 26, p 1177-1179. Unlike ordinary moles, dysplastic naevi are common on sun-protected skin. Like malignant melanoma, they are larger than moles, irregular in both outline and colour, but lack the distinct nodular development seen in MM (unless they themselves develop a focus of malignant degeneration), being macular (flat) or slightly raised (papular). Dysplastic naevi do show melanocytic dysplasia, and upper dermal lymphocytosis, do have a very significant premalignant potential; nevertheless, the majority of dysplastic naevi are stable lesions.cS / ON YY MCO / MA’ 26. Basal cell carcinoma 1. histlogically resembles keratoacanthoma 2. occurs more frequently in immunosuppressed individuals 3. occasionally occurs in the oral mucosa 4. usually occurs on sun-exposed skin Ans: (F, T, F, T) Robbins Sth Ed, Ch 26, p 1187. Immunosuppression is a risk factor. These lesions, while having a gamut of histologies, are distinctive cancers (not really resembling squamous carcinoma or keratoacanthoma) and do not occur in mucosae anywhere. The so-called "basaloid” carcinoma of the anorectal region should not be confused with this tumour. BCC have a particular feature of interest which Robbins does not mention - the mitotic rate is usually impressive, and so is apoptosis in the cancer cells 27. Merkel cell carcinoma of the skin: 1. isan indolent "adnexal" tumour resembling basal cell carcinoma in behaviour 2. histologically resembles "oat cell" bronchial carcinoma 3. most commonly arises in axillae, groins or midline anterior abdominal skin 4, shows both neuroendocrine and epithelial differentiation by cell marker studies Ans: (F, T, F, T) Robbins Sth Ed, Ch 26, p 1187-1188. Robbins pays this cancer scant attention and considers it to be rare. Not in our experience - unusual perhaps. It has a formidably aggressive biology, and morphologically resembles neuroendocrine cancers elsewhere in the body (“oat celi” cancer, carcinoids in various sites, islet cell tumour etc.). It is most commonly present in head and neck (and extremities) 28. Kaposi's sarcoma: 1. arises in skin and usually remains confined to skin and subcutaneous tissue 2. isles biologically aggressive when it occurs in HIV-positive individuals 3. presents as reddish, spreading and merging papules and plaques in the skin 4. isa suppressor T lymphoproliferative disorder Ans: (F, F, T, F) Robbins Sth Ed, Ch 11, p S11. This tumour is of, as yet undefined histogenesis. As seen up until somewhat over a decade ago in USA, this was an indolent tumour of ageing men of Mediterranean origin. As part of the AIDS syndrome, it is an aggressive skin neoplasm which fairly rapidly disseminates to the viscera. Itis almost certainly an endothelial sarcoma of some sort; certainly not a T lymphoma, 29. Multiple endocrine neoplasia syndromes may threaten life because they may cause: 1. hypertension 2. inappropriate ADH secretion 3. relentless peptic ulcer syndrome 4. “malignant” thyrotoxicosis (thyrotoxic storm) Ans: (T, F, T, F) Robbins Sth Ed, Ch 25, p 1169-1170. Phaeochromocytoma is part of the variations on the theme of MEN I; Zollinger-Ellison syndrome is part of MEN I. Inappropriate ADH secretion is seen with bronchial cancer (usually "oat cell" or a variant) or with hypothalamic pathology. Life-threatening thyrotoxicosis is seen only in Graves’ disease, which is not part of MEN. 30. Carcinogenesis induced by DNA viruses: 1. isusually a single step ("single hit") process 2. may act by neutralising the influence of growth-inhibiting molecules 3. may involve incorporation of viral oncogene into host DNA 4. may cause stimulation of the function of growth-promoting protein(s) Ans: (F, T, T, T) Robbins 5th Ed, Ch 7, p .286-290 Each of items 2, 3 and 4 is correct under different circumstances and with various viruses. However "studies provide firm evidence that cancer, even when caused by highly oncogenic viruses, is a multistep process". This section of Robbins also deals with other important concepts of viral oncogenesis - eg. the cell must survive the infection; early transcribed genes are essential for oncogenic transformation, they are incorporated stably into the host cell genome (andNCOL LM subsequent generations) and they interrupt the subsequent replication of the late viral genes, thus preventing assembly of the complete virus. 31, Inthe follow-up of asymptomatic family members of a patient with multiple endocrine neoplasia syndrome which includes medullary carcinoma of the thyroid (MEN T1), effective screening tests include: 1. plasma calcitonin levels 2. urinary catecholamine estimation 3. plasma calcium estimation 4. serum ionised calcium / phosphate ratio Ans: (T, T, F, F) Robbins Sth Ed, Ch 26, p 1169-1170. Despite the theoretical action of calcitonin on plasma ionised calcium, plasma calcium and phosphate levels are normal in this syndrome, even in the presence of a calcitonin-secreting medullary cancer of the thyroid with metastases. Urinary catecholamine determinations will often unearth an early phaechromocytoma. 32. Papillary carcinoma of the thyroid: can be the result of childhood thyroid irradiation may have lung metastases which are asymptomatic for many years commonly presents clinically because of metastases is biologically more aggressive, when the histology shows an admixture of papillary and follicular growth patterns Ans: (I, T, T, F) Robbins Sth, Ch 25, p 1137-1138. Papillary cancer follows childhood radiation like bills follow credit cards (sce question 1) There is no reason, with nuclear testing and nuclear energy plants, to feel confident that it will not increase in the future. This is an indolent cancer which has been likened in its biological behaviour to endometriosis; metastatic involvement is extremely common, sometimes widespread (even to lungs, brain! for many years) with minimal deterioration - however, needless to say, overall these are markers for a poorer prognosis. Over half of papillary carcinomas contain a histological admixture of follicular growth. However, long-term follow-up shows that "...regardless of precise proportions, all neoplasms containing some papillary areas have identical biologic behaviour..." Bene 33. RNA oncogenic viruses: 1. show evidence of causal involvement in the genesis of many human cancers 2. can convert normal host cell proto-oncogenes into oncogenes (c-oncogenes) 3. form templates for DNA transcription within the host cell 4. usually splice directly into the host genome before activation Ans: (F, T, T, F) Robbins Sth Ed, Ch 7, p 289-290. Only human T cell leukaemia virus (HTLV-1) which is, like HIV, strongly tropic for Ta/TH cells has been implicated in causing human cancer, although there are heaps of animal counterparts. They can act as oncogenic viruses only by incorporating a copy DNA (ie. mirror image of the virus RNA structure [response 4, but not response 3]) into the host genome. They ccan (indirectly) then activate host proto-oncogenes => c-oncogenes or possibly splice ina DNA copy identical to a host proto-oncogene into the wrong place where it acts as a c-oncogene (eg. too near an "activator" gene or too distant from a "controller/suppressor" gene). 34. Epstein-Barr virus (EBV): 1 binds to receptors on B lymphocytes 2. does not stimulate anti-EBV antibody in Burkitt's lymphoma patients 3. genome is present in most Burkitt's lymphoma cell lines in African patients 4° genome is present in most Burkitt's lymphoma cell lines in patients in USA. Ans: (I, F, T, F) Robbins Sth Ed, Ch 7, p 287-289. EBV is strongly B-lymphocytotropic, is a strong stimulus to the formation of anti-capsid antibody in both Burkitt's tumour developers and those who do not get the malignancy. ‘The EBV ‘genome is present in virtually all cases of Burkitt's lymphoma occurring in Africa / New Guinea; it is present in the genome of only the minority of morphologically identical (including chromosomal {{8;14] translocation) tumors occurring outside Africa (see also the comment on question 7).7 ae 35. Proto-oncogenes: 1. are rendered incapable of transcribing growth-related proteins following, chromosomal translocation Zz, are, in the normal cell, inactive DNA sequences without physiological action 3. may be activated into functioning oncogenes (c-oncogenes) by mutation of a specific gene site 4. may be activated by destruction of adjacent controlling genes, which normally suppress their action Ans: (F, F, T, T) Robbins Sth Ed, Ch 7, p 259 et seq. This looks like a formidable 10 pages. Response 1 is clearly false; gene sequences may be activated (removed from a "suppressor" or inserted near an “activator”) by translocation, In regard to response 2, proto-oncogenes are, in the normal cell, the activators and switches ("on" and "off") for normal growth. Responses 3 and 4 outline two of the ways in which normal proto-oncogenes may be influenced to become oncogenes (also referred to as c-oncogenes). (Cellular) oncogenes are perverted proto-oncogenes (growth genes). 36. Familial retinoblastoma: is always a congenital neoplasm is activated by chromosomal translocation inheritance pattern is autosomal recessive develops only in a retinoblast which has the appropriate DNA defect in both of the paired chromosomes Ans: (E, F, F, T) Robbins Sth Ed, Ch 7, p 265-266. Familial retinoblastoma is inherited, but not necessarily congenital. The inheritance genetics is of a single defective gene, which is protected by the paired gene in each retinoblast cell. However, all of the retinoblasts are “primed” by having one defective gene - mutation of the other gene in just ‘one retinoblast, removes all of that suppressor gene activity from that cell. If that retinoblast is still in the "replication pool", retinoblastoma ensues; if that cell has matured to join the ranks of permanent cells (differentiated), presumably cancer does not ensue. BONE QUESTIONS 37-44 CHOOSE =A if CrC_ B if CxC C if C-Wr Dif WCE if WrWr 37. Carcinogenic initiating agents are Careinogenic initiation produces thought to produce their actions beeause irreversible alterations in DNA by their mutagenic effects chemistry in target cells Ans: A (C-r-C) Robbins 5th Ed, Ch 7, p 280-281. Whether they act as complete, direct or indirect initiators, the action of carcinogenic initiators is presumed to be because they cause permanent alteration to the DNA, by an action which is rapid and irreversible. It also has "memory", in that a threshold dose is effective when given cither in a single dose or as divided doses. 38. DNA damage by chemicals is not because DNA damage can be repaired by necessarily carcinogenic cellular enzyme systems Ans: A (C-r-C) Robbins 5th Ed, Ch 76, p 282; Ch 9, p 402-404. The written evidence for this statement and reason is, perhaps, not as direct as T would like. ‘The evidence for repair of DNA following radiation injury is very strong. Single strand breaks are rapidly repaired (within minutes) and double strand breaks may also be repaired, usually less promptly. Some are inreparable - these may lead to cell death or become the initial steps of oncogenesis. By implication, the same should be true for chemicals, but a direct and definitive statement to this effect cannot be found in Robbins. 39. The effects of carcinogenic Tumours do not eventuate if the promoters are thought to be because "promoter-effective" dose is potentially reversible applied prior to the application of the appropriate initiatorAns: A (C-r-C) Robbins Sth Ed, Ch 7, p 280. Promoters are not electrophilic compounds and do not damage DNA. They induce clonal proliferation of initiated cells and alter their differentiation programmes. They appear to bring about these changes by the use of existing normal growth-promoting physiologic transduction pathways, not by inducing new ones. 40. The effects of carcinogenic tumours do not eventuate if the initiators on DNA chemistry is. because subsequent promoter application reversible is delayed Ans: E (F-F) Robbins Sth Ed, Ch 7, p 280-281. This is a central to the "initiator" and "promoter" model. Initiation is rapid, irreversible and has "memory" - ie. application of the promoter by appropriate method and amount is equally effective whether it follows application of the initiator immediately, or after a delay. The action of the promoter is, however, potentially reversible as shown by the fact that divided doses of promoter cannot be separated by too long an interval, or the promoter effect is lost - ie. repair has occurred between applications of the promoter. 41 Karyotype / chromosomal In certain types of human abnormalities are thought to bea because neoplasia, karyotype abnormality primary event in development of is non-random and common in many human neoplasms that tumour type Ans: A (C-r-C) Robbins Sth Ed, Ch 7, p 258. "karyotypic alterations...in many...cancerous cells..are gene changes present in all? .With each passing year, it becomes more certain that the malignant cells of most types of human cancers have chromosomal abnormalities and.....defects are consistent... The most common types of nonrandom structural abnormalities in tumour cells are: (1) balanced translocations, (2) chromosomal deletions, and (3) cytogenetic manifestat- ions of gene amplification. 42. Major karyotype / chromosomal In human neoplasms, any abnormalities are not thought (0 beeause karyotype abnormalities are be a primary event in human uncommon and always variable neoplasms within the same tumour type Ans: E (F-F) Robbins 5th Ed, Ch 7, p 257-259. See discussion for question 41 43. Gardner's syndrome is a clinically in Gardner's syndrome, the more sinister variant of familial _ because colonic malignancies occur, on polyposis coli (FPC) average, about one decade earlier than when FPC occurs alone Ans: C (I-F) Robbins Sth Ed, Ch 7, p 271; Ch 17, p 813-814; Ch 27, p 1265. 44. Gardner's syndrome is aclinically aggressive neoplasms, other than more sinister variant of familial because colonic carcinoma, may be the polyposis coli (FPC) factors which determine mortality in Gardner's syndrome Ans: A (T-r-T) Robbins 5th Ed, as for question 43. Because of the co-existence of other "tumours", Gardner's syndrome has a deservedly sinister reputation. The fatal problem in many of these patients becomes the intra-abdominal fibromatosis which often follows the surgery for polyposis and may not be clinically obvious before this. Regarding the time onset of the malignacies, there is no difference between those with and those without the extra-colonic manifestations. patients becomes the intra-abdominal fibromatosis which often follows the surgery for polyposis and may not be clinically obvious before this. Regarding the time onset of the malignacies, there is no difference between those with and those without the extra-colonic manifestations. 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