Neoplasia 2018 lecture 11. Dr H Awad FRCPath

Transcription

1 Neoplasia 2018 lecture 11 Dr H Awad FRCPath

2 Clinical aspects of neoplasia Tumors affect patients by: 1. their location 2. hormonal secretions 3. paraneoplastic syndromes 4. cachexia

3 Tumor location Even small tumors can be dangerous CNS tumors can cause increased intracranial pressure

4 Effects of tumors on the host/ location effect

5 Effects by hormonal secretions example pituitary adenoma can secrete ACTH and cause Cushing syndrome

6 Cancer cachexia = progressive loss of body fat with associated weakness, anorexia and anemia Cachexia is not caused by the nutritional demands of the tumor There is some correlation between cachexia and the size and extent of spread of the cancer.

7 Causes of cachexia Anorexia plays a role, however chemical factors are the main reason Cachectic patents have high metabolic rate, muscle wasting TNF produced from macrophages is probably the main factor for these changes Effects of TNF: 1. suppresses appetite 2.inhibits lipoprotein lipase ALSO: proteolysis inducing factor that breaks skeletal muscle by ubiquitin proteasome pathway is increased in cancer patients it causes muscle wasting

8 The only satisfactory treatment of cancer cachexia is removal of the primary tumor

9 Para-neoplastic syndromes = symptoms that cannot be explained by local or distant metastases or by hormones endogenous to the site of origin. These are usually caused by ectopic hormone secretion Most common para neoplastic syndromes: hyercalcemia, Cushing syndrome, and nonbacterial thrombotic endocarditis Most common tumors that are associated with paraneoplastic syndromes: lung, breast and hematologic malignancies

10 Hyercalcemia as paraneoplastic Caused by 1. PTHrP ( parathyroid hormone related protein) 2.TGF alpha activate osteoclasts and the active form of vit D 3.TNF and IL1 NOTE: Skeletal mets cause hyperkalemia but this is not a paraneoplastic syndrome

11 Paraneoplastic syndromes

12 Clinical

13 Imaging

14 Lab diagnosis of cancer To diagnose cancer you need correlation between : clinical, radiologic and lab methods Clinical: cancer presents as hard, fixed infiltrative tumors Radiology: X ray, CT, MRI, PET scans Lab: morphologic methods, tumor markers, and molecular diagnosis

15 Lab tests/ morphology Cytologic smear: cervical smear, sputum.. FNA= fine needle aspiration, if a mass is easily accessible like: breast, thyroid. Or accessible by imaging technique: under imaging guidance FNA can be taken Incisional biopsy: representative sample taken Excisional biopsy: all the mass removed, usually with safety margin Frozen section: for quick diagnosis while patient still on the surgical table

16 Clubbing of fingers is paraneoplastic, mainly due to lung cancer etiology is unknown

17 Cytologic smear = pap smear

18 FNA.. Breast cancer

19 Frozen section

20 Frozen section Used to decide management during the surgery

21 Incisional biopsy

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23 When you excise, excise with a safety margin

24 Other morphologic techniques Immunohistochemistry Flow cytometry

25 immunohistochemistry Certain stains used to determine origin of tumor EXAMPLES Detection of cytokeratin by specific monoclonal antibodies means the tumor is epithelial in origin Prostate specific antigen (PSA) detected in metastatic foci indicates that the tumor is of prostatic origin ( prostatic primary)

26 Flow cytometry Fluorescent antibodies against cell surface molecules are used to decide cell origin Used mainly for leukemias and lymphomas

27 Flow cytometry

28 Flow cytometry

29 Tumor markers Tumor markers: enzymes, hormones.. Cannot be used for definitive diagnosis of cancer But can be used for screening or to follow up response to therapy or detect recurrence

30 PSA as a tumor marker PSA( prostate specific antigen) can be elevated in hyperplasia.. No level ensures that the is no cancer.. It has low sensitivity and low specificity PSA good for residual disease or recurrence

31 Tumor markers CEA (carcinoembryonic antigen) raised in colon, pancreas stomach, and breast cancer. Alpha feto protein.. Hepatocellular carcinoma and yolk sac tumors CEA and alpha feto also increased in nonneoplastic conditions With treatment these markers disappear if they reappear this means recurrence.

32 Molecular diagnosis PCR: polymerase chain reaction can tell if a lymphoid growth is monoclonal ( neoplastic) or polyclonal ( reactive. It detects the special rearrangements of gene receptor antigens in B and T cells Also PCR and FISH can detect the presence of translocations important for tumor diagnosis.

33 Polymerase chain reaction (PCR) is a technique used in molecular biology to amplify a single copy or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence.

34 Molecular diagnosis can also be used for: 1. for prognosis: like her2/neu explained before. Her 2 positive tumors have poor prognosis 2. Detection of minimal residual disease. After treating CML.. Level of abl-bcr transcripts measured by PCR give indication of residual CML 3. Diagnosis of hereditary predisposition to cancer, example BRCA 1 if present you can give patient advice and offer prophylactic surgery 4. therapeutic decision making. Example :Lung Tumors with ALK mutation respond to anti ALK therapy, Melanoma with BRAF mutation respond to anti BRAF

35 Molecular profiling of tumors Expression profiling Whole genome sequencing

36 Expression profiling Allows measurement of level of expression of thousands of genes Extract mrna from normal and cancer sources Create complementary DNA (cdna) to those mrna Label the cdna with florescent nucleotide Mix cdna from both specimens and hybridize them in a gene chip Compare the gene expression in both samples This technique showed that B cell lymphomas that look morphologically similar are heterogeneous in their genetic expression

37 Whole genome sequencing Compare the genome of cancer cells to normal cells in the same patient to discover all the mutations present This is now possible with the next-generation sequencing technology There are two types of mutations in cancer cells: Driver mutation: mutations in oncogenes or tumor suppressor genes that cause the cancer.. These can be targets for treatment Passenger mutations: more than the driver ones and mainly involve noncoding DNA

38 Driver mutations are usually recurrent in certain cancers Eg: ABL BCR Other driver mutations are uncommon. Like ALK mutation in only 4% of lung cancer but important because anti ALK treatment can be given to those 4% Some passenger mutations can cause drug resistance

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