MOD 2 lectures (infectious agents & soft tissue tumors) Flashcards
What occurs during viral oncogenesis
virus inserts genome into host genome, virus enters latent state, early genes essential for transformation, then those cells replicate w virus
-virus can also insert next to proto-onco turning it into onco (insertional mutagenesis)
HPV
most common STI in world
which hpv cause benign squamous papillomas (warts)?
types 1,2,4,7
which hpv types cuase low risk geneital warts (condyloma accuminatum)
types 6 and 11
which hpv types can cause squamous cell carcionma of vervix, angogenital, and upper resp tract
16, 18, 31, 33, 35, 51
Why are some types of HPV benign?
benign hpv stays extrachromosal, doesnt integrate into host genome (but for cancer it does)
integration of HPV 16 and 18
HPV dna interrupted at e1/e2 rdg frame of viral genome, e2 suppr transcr of early viral genes E6/7, so now theyre over expressed
- E6 binds p53 and interferes with cell cycle reg, and E8 binds Rb and p21 and does same
- so HPV 16/18 cause overexpr of E6/7, which bind and degrade TSGs
Retinoblastoma (Rb)
-recap: Rb hypo-phos and bound to E2F, then prolif signal upregulates cyclin D1 which bind to CDK, and this coplex phosphorylates Rb, which now frees E2F to go to nucl and transcribe cell cycle progression genes
High-risk HPV
Rb and p21 degradation causes incr rel of E2F, so uncontrolled cell cycle
-p53 activated in resp to DNA dmg, so now DNA cant be repaired/no apop etc
HHV-4 aka EBV aka Epstein-Barr virus– what can it cause?
- causes infectious mononucl
- in africa causes BURKITT LYMPHOMA
- B-cell lymphoma in immunosuppressed
- also hodgkin lymphoma, nasopharyngeal carcinoma, NK/T-cell lympoma
MOA of EBV
targets orophar epith cells and B cells via CD21, EBV genome remains episomal in B cell, no rep, becomes immortalized
-LMP-1 (late membrane protien 1) viral gene can mimic activated CD40 and trick B cells into prolif as if stimulated by T cells (normal activation paths), stim of JAK/STAT etc, B cell prolif
Other cells involved in B cell immortalization in EBV
EBV nuclear antigen 2 (EBNA-2) activates cyclin D1 to promote cells to go from G0 to G, and incr transcr of LMP1
What does LMP-1 in EBV do overall
LMP-1 mimics helper T cell signal that stimualtes CD40, causing B-cell prolif
Burkitt lymphoma chromosomal translocation
8 and 14 (pathognomonic)
What causes burkitt lymphoma
EBV esp in african version (for most ppl EBV doesnt cause burkitt lymphoma if healthy immune sys)
what gene amplification causes all cases of burkitt lympohma
c-myc oncogene amplification
(on 8, translocated to IgH gene on chrom 14)
-polyclonal b cell mitogen, cell cycle checkpoints overwhelmed so translocations and mutations more frequent (worse for AIDS and immunosuppr/def)
burkitt sx
disfiguring jaw mass
what happens to EBV infected cells in transplant
undergo polyclonal b cell prolif, but immune sys eventually regresses them, if not they become monoclonal neoplasms (LMP-1 overexpr at first)
Nasopharyngeal carcinoma cause
100% contain EBV (incidence high in China, Africa, and Arctic)
HBV`(hepatitis B virus) assoc cancer
associated with HCC (hepatocell carcinoma) esp asia/africa (most HCC caused by HBV)
How does HBV cause cancer
insertional mutagenesis, (near protoonco), but more likely is chronic hepatocell inflammation and injury (bc more regeneration/cell div so more chance of mutation)
-or HBx prot (encoded by HBV DNA)
What does HBx protein do in HBV cancer
disrupt normal growth of infected liver cells, activates growht pormoting genes like IGF and binds p53 decr effectiveness and suppressing growth
What is an example of an oncogenic RNA virus
Human T-cell leukemia VIrus (HTLV)-1
What cancer is HTLV-1 assoc with/ sx?
Other assoc/location?
adult t-cell leukemia/lymphoma (ATLL), neoplasm made of flower-like lympocytes (look like purple flowers on slides)
-endemic in japan, carrib, and assoc with tropical spastic paraparesis (paralysis or weakness of lower extremities)
Which virus is assoc with weakness of lower extremities, and what is this sx called?
HTLV-1
tropical spastic paraparesis
How is HTLV 1 similar to HIV
infects CD4+ T cells, transmitted thru STI, v long latency period, only smol % get leukemia
What gene in HTLV-1 is essential for leukemic transformation
Tax gene (doesnt involve insertional oncogenes) Tax gene dysregulates cell cycle, inactivates cell cycle inhibs and enhances cyclin D, stops DNA repair and inhibits checkpoints!
H pylori bacteria and cancer assoc
curved gram neg bacillus assoc with development of gastric carcinoma and lymphoma
-dev of small B-cell lympohma of MALT (mucus assoc lymph tissue), 100% assoc
Pathologic features of H pylori
Tx
Tx with antibiotics
- lymph infiltration and lots of germinal ctrs, lesion on stomach, made of monocytoid B cells which look like fried egg and are CD20 positive
- lympoepithelial lesions are monocytoid B cells that invade and destroy gastric glands
H pylori MOA
irritates gastric mucosa, inflamm response, causing extra lympoid tissue to dev and B cell prolif, causing accum of mutations, dev of B cell lympohma
(metaplasia–>dysplasia–>invasive carcinoma)
What are tumors usually combatted by
recognized as non self by CD8+ cells, macros, and NK
- CD8 fight tumor ag expressed on MHC 1 and protecc against viral tumors
- NK cells destroy those that downreg MHC1
- macros work with both cells via IFN-gamma (prod by both cells)
Tumor immunology: immune surveillance and immunoediting
- immune surveillance: normal immune sys can destroy cancer
- cancer immunoediting: immune sys elim tumor variants that are unrecogniziable
What are the 7 categories of tumor antigens
1) Mutated oncogenes
2) Mutated self-proteins
3) Over-expression/aberrantly expressed proteins
4) Oncogenic viruses and associated tumor antigens
5) Oncofetal proteins
6) Abnormal cell surface glycoproteins/glycolipids
7) Differentiation agents
1 mutated oncogenes
processed by MHC I/II and destroyed by CD4/8 cells
2 mutated self proteins
radiation or chemical induced etc, same response as prev
3 over/aberrently expressed self prots
normal prots overexpressed, or embryo genes expressed during non embryo (if in tumor, immune sys will rec as aberrant)
4 oncogenic viruses and associated tumor antigens
viral tumros produced prots, recognized as foreign (latent DNA viruses like EBV and HPV are most potent) (eg vaccine allows immuen sys to make abs to HPV)
5 oncofetal ag’s
common tumor markers?
prots expr in embryonic tissue but shouldnt be in adult, some tumors make these so immune sys can recognize (but can also occur in inflamm)
-CEA and AFP commonly used as tumor markers
6 abnormal cell surface glycoprots/lipids
includes gangliosides, blood group antigens, and mucins CA125,CA19-9,MUC-1
- dont only mean tumors, but higher in cancer cells
- tumors may have weird carb side chains or weird peptide cores (targt of mabs and vaccines)
7 differentiation antigens
lineage specific antigens, can give mabs against these for immunotherapy (eg rituximab as antiCD20 for b cell lymphoma)
Why do ppl still get cancer?
tumors fail to produce ag’s rec by immune cells, hide surface antigens in glycocalyx molecs, reduced MHC expression or costim by tumor, tumor produces immunosuppressive prots, Fas ligand expression by tumor cells can cause T cell apoptosis
INfectious viruses (4) and bacteria assoc with cancer?
HPV EBV HBV HTLV-1 H pylori
What are the 3 categories of soft tissue tumors (from soft tissues neoplasia handout)
Benign
intermediate (locally aggressive and recurring but dont metastisize)
Malignant (sarcoma)
What is a soft tissue tumor called
sarcoma
Sarcoma features
oft in extremeities, below fascia, large, high mortality, ~10% metastasis
WHAT 2 FEATURES IS SARCOMA GRADING BASED ON
MITOTIC RATE
DEGREE OF NECROSIS
What env factor and what 3 syndromes are sarcomas assoc with?
- irradiation (10 yr)
- gardners syndrome (mesenteric fibromatosis)
- NF1 (schwannomas, malig nerve sheath tumors)
- Li-Fraumeni syndrome (p53, soft tissue/bone sarcoma)
Types of cells in soft tissue tumors
spindle cell (rod shaped, fibroblast/SM cell) round cell (small, lympho sized, little cytoplasm (ewings, rhabodmyosarcoma) epithelioid: round, larger w lots of cytoplasm (epith like)
Benign fibroblastic tumors
nodular fasciitis
fibromatosis
nodula fasciitis
benign fibroblastic tumor of soft tissue: subcutaneous (superficial) fast growing spindle cell lesion of extremities/trunk
-can be excised, recurrence rare
fibromatosis
benign fibroblast tumor (soft tissue)
locally aggressive lesion of fibroblasts, benign spindle cells set in collagenous background
fibromatosis IHC
BETA-CATENIN POSITIVE
fribromatosis types
superificial: plantar fascia, palmar fibrromatosis
deep: mesenteric (gardners), extra-abdominal desmoid type
Benign vascular tumors
capillary hemangioma (incl pyogenic granuloma) cavernous hemangioma
capillary hemangioma
incl pyogneic granulama
-hyper prolif of small vascular spaces, esp in kids, regress w age
cavernous hemangioma
Endoth markers?
large vascular spaces, doesnt regress, may be assoc with Maffucci’s
-Vascular tumors (+) for endothelia markers CD31 and CD34
Benign peripheral nerve tumors
Granular cell tumor
Schwannoma
Granular cell tumor
and IHC profile
benign neural tumor, round cells w pink cyto granules, positive for S-100 portein (schwann cell origin)
Schwannoma and IHC
benign PNS tumor with pallisading spindle cells, risk of malig transformation in NF1, acoustic neruomas in NF2, S100 positive by IHC
Benign adipocytic tumors
lipoma-most common soft tissue tumor, subcutaneous
intramuscular lipoma- benign but locally inflitrates SKM, rare recurrence
Malignant soft tissue tumors (sarcomas) list
DFSP (dermatofibrosarcoma) Fibrosarcoma Malign fibrous histiocytoma (undiff pleomorphic sarcoma) Liposarcoma (well diff) Synovial sarcoma Leiomyosarcoma Angiosarcoma Rhabdomyosarcoma
Dermatofibrosarcoma protuberans (DFSP) IHC and cells
int, rarely metas, nodular lesion superficial, prominent spindle cell storiform patterns
-CD 34+ spindle cells! (also expr by endoth cells)
Fibrosarcoma
middle aged adults, deep soft tissue exp extremities and trunk, fish-flesh appearance in high grade, hypercell spindle cell with herringbone pattern, no consistent IHC
malignant fibrous histiocytoma
undifferentiated pleomorphic sarcoma
-late adult life, deep soft tissue extrem and trunk, fibro/myofibro/blastic and plemoprhic histyocyte like cells, no consistent IHC
Liposarcoma (well-differentiated)
Which gene is amplified?
Myxoid variant translocation?
most common in middle age, deep tumor esp in retroperitoneum, lipocytes with enlarged nuclei (lipoblasts), supernummerary ring chromosomes
- MDM2 gene amplification (conventional)
- Myxoid variant has t(12;16) translocation
synovial sarcoma
IHC
translocation
young adults, knee/thigh/foot, biphasic epith/spindle pattern, rearr of SYT gene
- IHC epith markers CYTOKERATIN and EPITHELIAL MEMBRANE ANTIGEN (EMA)
- translocation x;18
- always grade 3
Leiomyosarcoma
IHC
malig SM tumor, spindle cells in fascicles and eosinophilic cytoplasm
IHC: smooth muscle ACTIN and DESMIN
Angiosarcoma
IHC
malig sarcoma of blood vessels, can be post radiation
IHC CD31 and CD34
Rhabdomyosarcoma
IHC
Types
Malig sarcoma of SKM, kids, can be spindle or round cell
IHC: DESMIN and MYOGENIN
-Types: embryonal (incl botryoides variant (grape like mass in GU of kids), alveolar (1 and 2;13 translocation)
+/- profile of sarcomas in general?
VIMENTIN POSITIVE
CYTOKERATIN NEGATIVE
where else does leiomyosarcoma occur?
Gi tract
deep soft tissue of extremities
retroperitoneum
Gardner’s syndrome Sx, and what is it a part of?
Gene involved?
Part of FAP (familial adenomatous polyposis)
Sx: colon polyps, abd desmoid fibromatosis tumors, skin fibromas, jaw pain/lesions, bone tumors (osteosarcomas)
-Gene: adenomatous polyposis coli (APC)
What gene is usually mutated in fibromatoses/desmoid tumors
BETA-CATENIN
Diffs between benign and malig soft tissue tumors
malig: doesnt resemble normal tissue, irreg nuclei (grainy), large, deep to fascia, necrosis, high grade
Fibromatosis can be assoc with
peyronies disease (penis plaque) and dupuytren’s contracture (trigger finger, invol)
- deep called desmoid
- mesenteric type can inv gardners (in mesentary or retroperit), abd etc
Other tumors
SKM: myositis ossificans
Glomus: modified SM cells, a-v anastamoses, females, triggered by cold temp or touch, thermal reg (benign)
-pyogenic granuloma (type of hemangioma), ulceration/inva, skin/gums/lips/tongue
Lipoma found in neck and back
Giant cell tumor of tendon sheath: fingers, yellow, histiocytes, lobulated mononucl appearance
-MFH: malig fibrous histiosarcoma: (undiff pleomorphic sarcoma) in extrem/trunk, radiation, fibro/histio cells, inflam
-angiosarcoma v aggressive
Which sarcoma is the only one that stains with epithelial markers>
synovial sarcoma
EMA and cytokeratin
What is an SKM marker
mygenin (eg rabdomyosarc)
