Heme/Onc Week 3

explain the difference bw staging and grouping for rhabdomyosarcomas? how do you tx? what are cure rates for non-met disease vs mets

"stage the pt" (where is the disease, where isnt it), "grade the tumor" staging: 1 = *orbit, non-PM head/neck, GU (non-bladder or prostate), biliary tract* 2 = other sites with no LN or mets 3 = either LN1 or >5 cm 4 = M1!! ~note: as you get older (10+), more likely to be stage 4 (25%) group: I = completely removed local tumor w/ no LN involvement II = local tumor; removed with micro margins, involved grossly resected LNs, or both III = localized tumor with gross residual disease, or only did a bx IV = distant mets at dx tx: surgery (really want complete resection! big influence on survival), radiation (except not group I!), chemo ~*60-70%* of non-met disease --> curable!! ~*<30%* with metastatic disease can be cured

Explain BRCA1 and BRCA2 and hereditary breast cancer syndromes -women and men!

-*BRCA 1/2* are *autosomal dominant* w/ *incomplete penetrance* and account for ~7% of breast cancer (most inherited breast cancers are not through syndromes) -lifetime risk breast is 80% and ovarian is 45%, -2% incidence in Ashkenazi/eastern european jews -may also inc risk for pancreatic cancer -Tend to develop in *younger* women and more often *both breasts*-->as well as ovarian also inc risk of colon & pancreatic cancers and melanoma -men w/ BRCA2 have 80x greater risk of breast cancer (8%) and 7x more likely to get prostate cancer -men w/ BRCA1 slightly higher risk of prostate cancer

Briefly explain melanoma (why is it so bad?)

-4% of malignancies annually -pT stage based on depth (Clark level/Breslow depth) and presence of ulceration -Thought to spread via lymphatics first (sentinel node) -Known to present with metastasis late -main reason its so scary is bc there is *poorly effective adjuvant therapy* (IL-2, BRAF-pathway modulators are in progress) -Metastectomies

Compare and contrast Carcinomas and Sarcoma

-Carcinomas are more common (epithelium is always dividing) -*SMOKING *is a major RF -Exceptions to lymphatic spread: *renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), follicular carcinomas of the thyroid* which spread hematogenously -sentinel LN very imp (if neg all are) -distal mets are often to the first small vessel "filter"-->GI goes to liver, prostate goes to bone, others go to lung -Sarcomas are divided based on risk of bad behavior, invasion is not super important, more about definitional features (*necrosis, atypia, mitotic rate*) and metastasis -benign--->do not recur after complete excision -intermediate-->destructive growth or high risk of local recurrence or rare ability to metastasize -malignant--> above + *substantial risk of mets* -usually spread hematogenously (*MC lung, bone, brain*) -up to *50% w/ prior radiotherapy* -usually malignant from development (don't transform)

Explain how breast cancer presents

-MC presentation in US: *abnormal mammogram* -Palpable mass: needs to be *~2cm*, ~15% present w a palpable mass that is not detected on mammogram ("mammographically occult disease"), ~30% present w a palpable mass between mammograms ("interval cancers"), PE cannot reliably differentiate benign vs. malignant (but hard, fixed, irregular mass points that way) -only 5% of DCIS is palpable, usually detected as *calcifications* on mammogram other findings: -*UOQ* is 40-50% of cases -Skin changes (*peau d'orange* dermal lymphatic spread) locally advanced disease/BAD -nipple Discharge (rare) or retraction -Stigmata of metastasis (example = pathol fx) -nodal mets (lung, liver bone)

Explain how tumors present in general

-MC presentation is incidental, and if S/S are present they directly or indirectly relate to the tumor mass -direct: mass effect (malignant or malignant that might be palpable and compress/obstruct adjacent structures) -indirect: "humoral" factors, may be the first presentation; cachexia (TNF-A), paraneoplastic syndromes, hematologic (anemia, thrombosis, DIC), ID w/ opportunistic infections

Explain risk factors for breast cancer

-Sex (99% female) -race/ethnicity (white more likely but AA more aggressive), geography -age (MC in late 50s-mid 60s) -*estrogen exposure* (HRT/obesity) -reproductive hx: late or no pregnancy, early menarche, late menopause (note breast feeding is protective) -affected first degree relatives 2x risk (*FHx very important*) -lifestyle: late onset obesity (incs relapse risk also!), alcohol, no exercise, poor diet -radiation -benign breast disease: fibrocystic breast disease (inc 1.5-2%) and atypical hyperplasia (inc 4%), having dense breasts, LCIS -genetics: BRCA 1/2, TP53, CHEK2 -past history of breast cancer (3-4x) -low vitamin D levels -drugs: DES exposure -BUT 85% of breast cancers are dx in women w/ NO RFs!! -can assess overall risk with the modified gail model -remember smoking is *not* a RF (except it is according to new lecture)!

Explain basics of breast cancer staging and different prognostic factors

-Size, extension into adjacent structures= T (<2 is T1, 2-5 is T2, >5 is T3, and into chest wall, skin and inflammatory is T4) -LN status: number/size=L (in breast cancer, designate if there is <.2 mm/no more than 200 cells detected by H&E or IHC as i+, then positive LNs can be *micro or macro*, N1Mi is micro, N1 is 1-3 LNs and one must be macro, N3 is 4-9, and N3 is >10) -metastatic disease (distant, >.2mm) -peu d' orange is a bad sign, makes it T4 -one of the only one where you can have *N1 and be stage 2*

Explain basics of what personalized medicine means in oncology

-Using info about gene expression status in a tumor or patient's germline to dictate therapy or modify prognosis-->Abnormalities in different genes present different therapeutic targets -Different philosophy than tumor staging, --Former paradigm: all x tumors get a specific chemotherapeutic protocol --Current paradigm: therapy protocol dictated by specific tumor phenotype -ex KIT mutations in GIST and MSI/BRAF in colon adenocarcinoma Explains tumor pathogenesis, potential tumor syndromes, and stage for stage better predicts survival

Can you prevent breast cancer?

-Yes, *tamoxifen* does prevent in HR cases, determine who is HR by the gail model, calc risk using 6 key RFs (age, age menarche, age first birth, family hx esp of 1st degree female relatives, number of previous breast biopsies, and number of biopsies w/ atypical hyperplasia)

Explain male breast cancer?

-anatomy has a nipple/duct system simialr to prepubertal female breast, but there is *no significant lobular formation* (no TDLU!) -.1% incidence (compared to 13% for women) -prognosis is similar to female stage to stage but it often presents in *high stage* as its easier to be involved in skin/chest wall bc male breast is smaller RFs: Older age, FHx, ↓ Testicular function, Exogenous estrogens, Radiation, Obesity, Western country, *BRCA2* (10% of male cases), *Klinefelter's* -NOT gynecomastia Tumor types -DCIS -Invasive ductal carcinoma/NST: MC type of invasive breast cancer in male, Usually presents as *subareolar* 2-3 cm mass, 50% have positive nodes at time of diagnosis -Special types (similar to female): Rare in-situ and invasive lobular carcinoma (remember male beast develops very few lobules), 80% are ER+

Explain the major pathways of breast cancer development and basics of breast cancer classification

-former concept of development simply had an ER- pathway that was more aggressive and an ER+ pathway with a better prognosis -Now there is an *ER+* pathway (50-65% of cancers) started with a germline *BRCA2* mutation, a *HER2+* pathway (20% of cancers) starting with a germline *TP53* mutation, and an *ER-/HER-* pathways (15% of cancers) starting with a germline *BRCA1* mutation Adenocarcinoma is >95% of malignancy, most arise from TDLU -CIS can be ductal (DCIS) or lobular (LCIS) + is confined to the lumen/lacks metastatic potential -invasive can be ductal (or NST, 80%), special type (10%) of which lobular is the MC (10%)

Explain basics of normal breast anatomy and histology

-modified apocrine sweat glands, bilateral, extends into axilla -central nipple/areola and the breast is divided into four quadrants (UOQ, UIQ, LOQ, LIQ; UOQ is ~45%) and lesions are often described using the clock method (Ie lesion in the right UIQ at 2 o clock 3cm from nipple) to be as specific as possible -two types of stroma: intralobular that is hormonally sensitive and interlobular that isn't (breast tissue in general is responsive to hormones, hence lifetime changes) -skin-->subQ fat-->lobules and coppers suspensory ligaments-->fat, lactiferous ducts, ampulla (lactiferous sinus) and acini -Large Duct system, the terminal ductal lobular unit *TDLU* is very important as most adenocarcinomas arise from it -TDLU (lobule makes milk, drains into terminal ducts)-->subsegmental ducts-->segmental ducts-->lactiferous ducts-->ampulla/lactiferous sinus -the glands/ducts are lined by two layers of cells-->inner *luminal epithelium* and outer *myoepithelium* (if myoepithelial layer is present it is a benign gland!! They are lost in malignant infiltrative glands) LNs: axillary, internal mammary, and intramammary -level I-III axillary nodes, the higher the number the more superior & the worse it is -lateral 1/2 of breast drains toward axillary; medial 1/2 to axillary & internal mammary chain; intra in UOQ

What pathology can occur in the interlobular stroma?

-myofibroblastoma: both M/F, general benign tumor of myofibroblasts -lipoma -angiosarcoma: sporadic or therapy relation (radiation/chronic edema) -pseudoangiomatous stromal hyperplasia -fibromatosis

Explain the following special types of invasive mammary carcinoma -medullary carcinoma/carcinoma with medullary features

-often in *younger* females (45-52) -<1% of all breast cancers -soft round circumscribed mass -*BRCA1* association -- 13% of tumors in BRCA1 carriers; 60% have some medullary features -usually *triple negative* (ER/PR/HER2) with *"basal like"* gene expression profile Diagnostic criteria a) syncytial architecture (irregular sheets/islands) in >75% of the tumor mass b) histological circumscription or *pushing margins* c) lack of tubular/glandular differentiation, d) a prominent and diffuse *lymphoplasmacytic* stroma infiltrate e) tumor cells with grade 2 to 3 nuclei (high grade vesicular nuclei containing one or several nucleoli) Most studies show *good prognosis* as compared to invasive NST, but this is confounded by use of different classification systems (i.e. if it meets some but not all criteria is it included or not?) and inter observer variability -good prognosis thought to be due to lymphoplasmacytic infiltrate representing host response to tumor Ag

Briefly explain how breast cancer management has changed and what current thoughts are -surgery -adjuvant chemo -hormonal agents -cyclin dependent inhibitors -neoadjuvant

-radical mastectomy used to be standard, then became modified, now lumpectomy + axillary LN dissection is standard -systemic therapy-->eliminates hidden microscopic disease and prevents systemic/local relapse, need to access R&Bs esp risk of release, can use molecular tools! -Adjuvant chemo: improves DFS and OS, use mult. drugs for 3-6 mo -anthracycline + taxane> anthracycline > CMF -hormonal and chemo benefits are *independent* Hormonal agents: -tamoxifen: risk of blood clots, uterine cancer, inc LFTs, cataracts, hot flashes but improvs BMD in post menopausal, improves lipid profile -Aromatase inhibitors: myalgias/arthralgias, dec in BMD, elevate BP/lipids/CV risk Cyclin dependent inhibitors-->prevent progression but won't melt away tumor like chemo (monitor *progression free survival*) Neoadjuvant: for inoperable tumors, inflammatory breast cancer, consider to inc chance for BCS (esp consider for triple neg) -no diff in DFS/OS b/w adjuvant and neoadjuvant Rx -can know if tumor is responsive to chemo *before surgery* -not good for ER/PR+ cancers

Explain basics of therapy and survival for cancer

-remember, cancer must transform-->grow-->invade/met Must assess patient goals/condition and disease biology: -Curative- eradicate cancer completely (aggressive) -Disease-free survival -Palliation- focus of treatment on relieving symptoms/increasing quality of life Three main treatment modalities -Surgery: physical removal, maintain of curative therapy in >90% of solid tumors, can do adjuvant therapy after or neoadjuvant before, inoperable tumors are not amenable to physical removal due to location/size (consider neoadjuvant!), pt status, or lack of remaining fxn -Chemotherapy: chemicals to kill rapidly dividing cells -Radiotherapy: radiation to induce cell death -Emerging modalities: Immunotherapy + Nano medicine Survival rate= statistic level abased on group of pts with certain disease characteristics and standard or care -Disease-free survival (time or rate; % disease free at ____ time) -Median survival (time) -Overall survival (percent.. often % 5yr) -Time to recurrence -all cause mortality Survival curve is a summary of pattern survival rates over time, can be uncensored (all pts observed until endpoint) or censored (die of unrelated cases or lost to f/u not included) -performance status is also used (karnovosky MC)

Explains basics of what is breast cancer -type -precursor -behavior & general receptor expression

-usually means *invasive adenocarcinoma* and that comes in two flavors: *Ductal* (~85%, look for ductal structures) and *lobular* (~15%, look for indian filing) ~sarcomas are RARE in the breast... either metaplastic carcinoma OR overgrowth of phyllodes tumor -precusors: *DCIS*, ductal carcinoma in situ, precursor to *both types* -lymphatic spread, axillary LNs (sentinel LN), may met to bone (blastic, sometimes lytic too) -most are hormone responsive, express *ER/PR* receptors (>70-85%), target for *SERM therapy* -18-25% express *Her-2/neu* gene, which is a target for *trastuzumab* -often described based on ER/PR and Her, triple negative is bad!

what are the MC pediatric cancers? why does it matter? what are the 7 "small round blue cell tumors"? ~how should they be worked up

1. acute leukemia (ALL > AML, 4:1) 30% 2. CNS tumors 20% 3. neuroblastomas 7% then... lymphoma, wilms, HL, rhabdomyosarcoma, retinoblastoma, osteogenic sarcoma, ewings cancer is leading cause of death (after accidents) in kids 1-14 yo ~1.7k per year (vs 500K in adults) ~but treatment saves 400K years of life (2nd only to breast ca) 1. leukemia 2. lymphoma 3. wilms 4. neuroblastoma 5. ewings/peripheral primitive neuroectodermal tumor (remember, t 11;22) 6. rhabdomyosarcoma 7. medulloblastoma ~workup: gross, micro (H&E, immunohistochem), cytogenetics, molecular, EM ~*tumor specimen should be picked up FRESH by pathologist*

what are the 4 options of mammographic densities?

1. almost entirely fat 2. scattered fibroglandular densities 3. heterogeneously dense 4. extremely dense *dense breasts lower sensitivity of mamm & inc risk of cancer (4-6x)!*

what are the 2 main appearances of cancer on mammo?

1. pleomorphic or linear branching microcalcifications (usually DCIS) ~calcifications can be benign... but if they are new or look suspicious, followup! 2. irregular or spiculated high density/white mass (invasive cancer) or architextural distortion

describe breast biopsy?

3 types of *core needle bx*, which are all preformed by the radiologist! ~note: always place marker clip into cavity & do post-proc imaging to document 1. US-guided core needle bx = MC ~targets *solid & cystic* masses ~15-20min, 2-5 cores w 12 gauge needle --> marker clip placement ~well-tolerated; local anesthesia in supine position ~takes 3-4 days to get results 2. stereotactic bx = 2nd MC ~targets *microcalcifications* and lesions not visible by US ~prone or sitting; can be uncomf for older/obese pts ~20 min *stereotactic bx w 30 tomosynthesis* = replacing prone 2D; pt sitting or laying on side & better tolerated; 10-20 min; can target *ANY breast lesions* (mass or calcs) 3. MRI guided ~targets lesions only visible by MRI ~prone & pts must be MRI-compatible (no pacers/metal in body) ~45-60min; may be difficult (prone, hold still, long, IV)

_____ % of women survive a breast cancer dx _____ % of women w one breast cancer will develop a second in the opp breast is mastectomy better than lumpectomy? is breast surgery urgent?

70-80% only 3% so getting double mastectomy is not smart; treat the cancer and do chemo & hormone blocking drugs ~only women with bad genes (5% of breast cancers) have inc risk (40%) of getting ca in other breast NO. same mortality of BCS/breast conservation surgery (lumpectomy + radiation) ~also, even if you have mastectomy, might need radiation and recurrence might actually be lower with lumpectomy/breast conservation than mastectomy no. palpable breast cancer has probably been there for 1-2 yrs and chemo should be used to shrink tumor while addressing other questions before surg

Explain epidemiology of breast cancer?

>90% in women, MC malignant tumor in women after skin cancer, accounts for 32% of all cancer and 15% of cancer deaths -*incidence 1/8 women* -High rates in north america, northern and western Europe, Australia, and parts of south america -low in japan, africa, and asia but rates for japan and china are inc -immigrant populations assume risk of immigration country -incidence in the US is *decreasing* maybe due to inc in mammograms, alterations in OCPs and dec in use of HRT but this is leveling off and might be due to lead time bias (detecting earlier)

Explain the luminal A vs luminal B molecular classification

A: • ER+, HER2-, *low* proliferation -MC subtype in *older women* and *men* (40-55% of all breast cancers) -LG, Good prognosis, Respond well to *hormonal therapy* (but *NOT* to chemotherapy!) B: ER+, HER2-, *high* proliferation -10% of all breast cancers -ER and PR expression may be low -MC type associated with *BRCA2* (15-20% of breast cancers) -More aggressive tumors compared to Luminal A: HG, Higher recurrence rate, Lower survival rate, Lower sensitivity to hormone therapy -BUT 10% show complete response to chemotherapy-->indication of much better prognosis than patients that do not respond

What is the most accepted staging system?

AJCC is the accepted means for most trails, based on populations and "statistical lines in the sand", basic idea is tumors of the same anatomic site and histo share patterns of growth/outcomes -TNM, pTNM is pathologic and trumps cTNM which is clinical based on imaging, PE, etc. -pTNM is now affected by molecular tools but accurate histo assessment with grading and tumors constitutes the bulk of info needed to prognosticate a given pts cancer and is the most cost effective T: tumor size/extension T0-T4 (*0 is usually IS, 4 out of organ*) N: LNs N0-N3 (+ LNs usually mean stage 3) M metastasis M0-M1 (+ usually means stage 4) -different rules for each organ and it is converted to stage depending on location to primary -biggest drop is b/w stage 2-3

Explain Fibroadenomas vs phyllodes tumors? BOTH biphasic lesions of the intralobular stroma!

Adenoma: -Benign biphasic tumor, Stroma (normocellular) & ductal epithelium -*Reproductive Age*, MC benign tumor (20-30), hormonally sensitive -Single or multiple -Gross: Spherical, *Circumscribed*, ~1 - 4 cm -histo: ductal structures still intact but stroma is proliferating Phyllodes: -Fibroepithelial neoplasm characterized by a *hypercellular* stromal component and *leaf-like* growth pattern -middle aged women, often >4cm -Gross appearance: well circumscribed, whorled appearance, cleft-like spaces resembling leaf -Classified into benign, borderline and malignant 1. benign: circumscribed, mildly inc cellularity/mitosis, local recurrence 10-17% 2. malignant-->*infiltrative*, greatly inc cellularity and mitosis, local recurrence 23-20%, distant metastasis to lungs/skeleton (sarcomatoid, hematogenous)

define: 1. Beckwith Weidemann syndrome 2. WAGR syndrome 3. Denys-Drash syndrome

BWS = wilms, macroglossia, organomeg, hemihypertrophy (*WT2 mut*) WAGR = wilms + aniridia + GU malformations + retardation (*WT1 del*) DD = wilms, early-onset nephrotic syndrome, male pseudohermaphroditism (*WT1 mut*)

what is BI-RADS and describe it

Breast Imaging Reporting and Data System ~example: if mass is seen on a screening --> at first is *0*!; do diagnostic mammo & US before you can call it a *5*!; *6* = post-biopsy note: cat 0 requires additional workup; 1/2 just routine; 3 FU soon; 4/5 do bx; 6 confirmed ca

Explain basics of DCIS (also called Intraductal carcinoma) and LCIS and what the difference is between them even though they both arise from TDLUs

DCIS: 15-30% of mammogram detected cancers (*micro-calcifications* usually one duct system) -bilateral 10-20% -has different histologic architectural patterns: solid, cribifrom, papillary (true vascular core) and micro papillary (also comedo) -precursor to both lobular/ductal invasive cancer -prognostic factors--> necrosis, nuclear grade, extent/size, margin status LCIS: often incidental and uncommon (1-6% of all carcinomas) -80-90% are in *premenopausal* women and it is *bilateral* in 20-40% of cases (also more common to be multicentric/focal) -not really a precursor, but is a RF for invasive carcinoma (25-35% of women >20-30 yrs, rate of ~ 1% / yr) and *both breasts* are at *equal risk* usually just watch and don't worry to much about margins since often indolent -*loss of E-cadherin* (16q CDH1) expression which is a transmembrane protein that contributes to the cohesion of normal epithelial cells, TSG in breast

Compare ductal and lobular invasive mammary carcinoma (remember lobular has subtypes) List the types of the other special invasive mammary carcinoma, besides lobular

Ductal: 80% -non-specalized pattern in >50% of the tumor, do not fit into any special type -tubule/nest formation, solid growth pattern (better diff will form more glands) -positive E-caherin -MC met is to lung Lobular: 10% -classic type: smaller, non-cohesive cells with low nuclear grade in *single file* (other variants: solid, alveolar, pleomorphic, tubolobular and mixed) -more often *bilateral* and multi-centric/focal -*negative E-cadherin* (CDH1)/discohesive cells -almost always Her2/neu- (rarely +, if so more aggressive) and ER/PR+ -Met to weird places (meninges, peritoneum, GI tract, ovary, uterus) -classic type has best prognosis of the subtypes, in general better ST survival but similar or even worse LT prognosis when compared to ductal/NTS Special: 10-15% -Tubular, Invasive Cribriform, Mucinous (Colloid), Invasive Lobular, Medullary, Micropapillary carcinoma

Compare HER2+/enriched molecular classification to ER- HER2-/ basal like?

HER2: ER+low/-, HER2+ -20% of breast cancers -MC subtype in germline mutation of TP53 (*Li-Fraumeni syndrome*) -More aggressive biologic and clinical behavior: HG (>75%), p53 mutation (40%), can met when small/early in course -Her2-targeted therapy: *trastuzumab* (Herceptin), Markedly improved outlook BUT may develop resistance to treatment Basal: ER-, HER2- -Independent of ER-mediated changes in gene expression and Her2 gene amplifications (i.e. not exactly the same as receptor studies showing a triple neg tumor) -15% of all breast cancers -MC in *young/premenopausal* women -MC type in *BRAC1 deficient* tumors -HG with lymphocytic infiltrate and medullary features -Poor prognosis-->Metastasize early (viscera, brain), Recurrence usually within 5 years, 30% may complete respond to chemotherapy

Explain the following special types of invasive mammary carcinoma -mucinous (colloid) carcinoma -invasive micropapillary carcinoma

MC: Can be pure (> 90% of mucinous component) or mixed -2% of all breast carcinomas -Often occurs in *older females* (> 55 years) -Soft gelatinous mass that is Slow growing + circumscribed; "tumor cell clusters floating in mucus pool" -*Good prognosis* (10 yr survival > 80%) for pure, Worse prognosis for mixed IMC -Can be pure (rare, .9-2% of all cancers) or mixed -Mean age of presentation similar to ER+ invasive carcinoma NST -Majority of cases are *ER+/PR+*, Her2+ in 10%-35% of reported cases -More frequently present with *lympho-vascular invasion* and *LN mets* (~75%) -Micropapillary feature as an independent prognostic factor remains to be determined -histo: hollow or morula like aggregates of cuboidal to columnar neoplastic cells surrounded by empty stroma

describe mammography ~screening vs diagnostic (3 reasons for dx) ~new 3D Digital Tomosynthesis note: other imaging techniques = US (handheld preferred), MRI (screening and dx), Breast PET, & Nuclear medicine

Mammo: ~sens 70-80% (depends on breast density.. >90 in fatty, 30-59 in dense); spec 80-90 ~22-35% red mortality in 50-74 yos, 25% in 40-50yos ~4-5 per 1000 detection rate ~costs $250-300 Screening: ~2 xray views of each breast (craniocaudal & mediolateral oplique angled toward axilla) ~small radiation dose 0.3-.4 mSv Diagnostic: ~used when pt recalled due to abn mammo (use spot compression or magn views), workup of breast problems (lump, pain, etc... *M & F*), and for all implants *3D Digital Tomosynthesis* = takes 15 pics in 4s in a 15deg arch ~20% of cancer isnt visible on 2D mamm ~enhances lesion detection, better margin analysis; improves spec (*reducing FPs*), and reduces recall rate ~finds up to 41% more invasive cancers ~useful for screening & diagnosis

Explain the following congenital/developmental conditions of the breast -milk line remnants -nipple inversion

Milk line remnants -breast cells form a line from the axilla to perineum, normally all cells regress except those that go on to form normal breast, in this condition some stick around -they can from an extra nipple (*polythelia*) or breast (*polymastia*) -odd locations for breast disorders, sometimes painful premenstrual enlargement Nipple inversion -can be unilateral or bilateral -usually little clinical significance and can sometimes spontaneously correct during pregnancy -if acquired can be due to tumor/inflammation (needs attn)

what is MIBB and what are the benefits?

Minimally invasive breast bx ~est pre-op dx of cancer, reduce surgical procedures needed and reduce pts with positive margins/inc rate of BCS ~can be used for both palp and non-palpable abnormalities ~can select pts who would benefit from neoadjuvant chemo... (triple negs, especially bc they are most assoc with BRCA1 so higher risk of other breast) ~accureate sentinal node mapping core needle samples are smaller than mammotome samples ~FNA is 97% sensitive, 78% spec ~core bx spares majority from surgery (best biopsy to get for breast cancer!)

Explain what is meant by molecular classification of breast cancer

Molecular subtypes of invasive carcinoma -Luminal A (*ER+*, HER2-, *low prolif*, Grade I-II): 40%-55% -Luminal B (*ER+*, HER2-, *Ki67/high prolif*, Grade III): 10% -Her2 (ER+low/-, *HER2+*, Ki67/high prolif): 20% -Basal-like (*ER-, HER2-*) :15%; Gene Expression Profiling -expression of genome by RT-PCR and mRNA microarray -Classifies breast tumors based on expression of ER, HER2 and proliferation genes into good, intermediate, and poor categories -Predict clinical outcomes (recurrence, how much radiation should you give?) -OncotypeDX, MammaPrint -Prognostic information largely stems from ER positive tumors, so if tumor is triples negative probably won't give you the best info -most useful for *small tumors w/o mets*

Explain inflammatory carcinoma (note not a specific histologic or molecular type)

Rare but very aggressive form of tumor (T4d carcinoma) that requires distinct *clinical* and *pathologic* criteria ~due to invasive breast cancer that has extended into dermal lymphatics -clinical: Enlarged breast with diffuse erythema and edema (*peau d'orange*) involving 1/3 or more of the breast skin -path/Microscopic features: Often high grade invasive ductal carcinoma, *Dermal lymphatic invasion* Very poor prognosis; many have distant mets

Compare the molecular subtypes of breast cancer?

Remember this table has exceptions, ex. most but not all basal-like carcinomas are triple negative (i.e. receptor study IHC that shows no expression of ER/PR/HER2)

Explain Pagets disease?

S/S: red, crusted, nipple/areolar skin -intraepidermal spread of tumor cells (pagetoid spread of pale tumor cells, migrate through subareolar duct) >95% associated with underlying breast carcinoma (unlike pagets of vulva) and prognosis is related to underlying lesion -invasive NST (53-60%) -DCIS (24-43%)

Explain Soft tissue sarcoma treatment and prognosis What about bone sarcoma?

ST: surgery is mainstay for cure -Benign- excise with negative margins -Intermediate- wide local excision (rim of normal tissue) -Malignant-- Usually neoadjuvant radiation, Allows for limb salvage (90%), same control rate as amputation, Should be done by specialists, Chemo only given for certain subtypes --overall 5yr survival of pts with sarcomas of all types *50-60%*, most die of mets found w/in 2-3 yrs of dx in 80% BONE: -XR and incisional biopsy for diagnosis with MRI -Neoadjuvant chemotherapy and repeat MRI -Resection with wide margins (Limb-salvage more common) -5 year survival-->*60-70%*

what are screening recommendations for breast cancer... how good is a mammogram? BIG take away for any mass?

Screen with self breast exam, provider exam, mammogram US, MRI in HR... for those with neg fam hx: -women >/=40: annual mammogram, annual clinical exam, month self exam (optional) -women 20-39: clinical exam every 3 yrs, monthly self exam (optional) Mammogram: *single* one has *<50% sensitivity*, NOT GOOD, needs to be repeated annually (women >50 skipping one yr can result in 30% of cancers being missed) -increases detection of small tumors and DCIS (due to micro-calcifications) -50% of tumors are >1cm at dx and 40% of tumors are node positive -Misses *10% of all tumors* even palpable! ALL PALPABLE MASSES REQUIRED INVESTIGATION (further imaging + bx) whether they are seen on mammogram or not.

Explain the basics of Solid tumors and what ones are most common?

Solid tumors = carcinoma, sarcoma, and melanoma (and CNS) -NOT hematolymphoid neoplasms (8% of annual cancer) KIDS 0-14: ALL> brain/CNS > neuroblastoma ADOL 15-19: HL > thyroid > brain/CNS ADULTS: MC is prostate/breast >lung/bronchus >colorectal and deaths is lung/bronchus > breast/prostate> pancreas

what is the staging for Wilms tumor and the other prognostic features

Stage 1 = *kidney* limited 2 = beyond kidney, but can be completely *excised* 3 = *residual* tumor, confined to abd 4 = hematogenous spread to *lungs* 5 = bilateral (rare!) note: new tx modality introduced at Stage 3 --> radiation! prognosis: ~histo: favorable > focal anaplasia > diffuse anaplastic; make sure its not clear cell tumor/rhabdoid tumor bc they have worse prognosis ~*loss of heterozygosity at 1p & 16q* --> both loci is the worst; no loci is worse than one if stage 3/4

Explain surveillance after breast cancer and general principles of metastatic disease?

Surveillance -Hx/PE every 4-6 mo for 5 yrs than annually (CBC/CMP and always as about mental and sexual health!) -mammogram annually and at 6 mo after treatment with XRT and breast converting surgery -pelvic exam annually for women with intact uterus on tamoxifen -other imaging only as indicated by Hx/PE Metastatic disease -hormonal therapy for indolent disease, trastuzumab therapy for HER2/neu+ disease, single agent chemo for aggressive/symptomatic disease or disease no responsive to hormones, polyagent chemo for visceral crisis or disease requiring rapid response -bevacizumab not really use any more (lost FDA approval for breast cancer)

Explain the following special types of invasive mammary carcinoma -tubular carcinoma -invasive cribiform carcinoma

TC: uncommon overall but up to 10-20% of breast cancers mammo detected, <1.0cm -Well differentiated/Grade 1: well formed tubules w/o myoepithelial cells, >90% of the tumor -Always ER+/PR+, typically Her2 - -*Excellent prognosis*: Low risk of local recurrence and distant metastasis ICC: -Invasive cribriform pattern in >90% of the tumor (back to back glandular formations w/o intervening stroma), p63+ -Frequently mixed with tubular carcinoma (TC) & biologic behavior is similar -if 10-49% of another morphologic type (other than TC) called mixed type carcinoma with cribriform features -*Excellent outcome*: 10 yr survival (90-100%), good prognosis even with a few positive nodes -Pure ICC> Mixed ICC> invasive carcinoma NST

how are US and MRI used for breast cancer?

US: ~not well-studied as stand alone tool, usually used after abn mammo OR if woman presents with lump then done with mammo ~differentiates *solid vs cystic* (CYSTIC is black fluid, with circumscribed margin!! SOLID is hypoechoic but irregular), helps with shape/margin assessment, axilla eval; helps with bx planning ~$500 MRI: ~sens up to 99% when combo with mammo; spec may be as low as 60% ~used to *screen HR* women yearly (esp with poorly informative mammos), *stage* newly dx cancer, for *silicone implant rupture*, for pts with abn phsycial exam but nl mammo/US ~$4000; have to lay prone

what are the two options when talking about childhood brain tumors? remember, 2nd MC peds cancer!

WHO grade I = *pilocytic astrocytoma* ~benign, good prognosis; GFAP+ with Rosenthal fibers (eosinophilic, corkscrew) WHO grade IV = *medulloblastoma* ~MC brain tumor in kids! highly malignant ~med age *5yo*; 2:1 M>F ~features: (not seizures) N/V, headache, ataxia, papilledema (inc ICP), non-communicating hydroceph (compresses 4th ventricle); may send *drop metastases* to SC ~bx: small blue cells! also homer-wright rosettes remember... pediatric brain tumors are often in *posterior fossa*, near brainstem & cerebellum; whereas adult brain tumors in cerebrum

Briefly explain how the following effect prognosis ~ER/PR/HER2 expression on receptor studies/IHC ~stage ~list other factors

Worse stage= worse survival (1=84%, II=71%, III=49%, IV=18%) -most *recurrences* occur *within 5 yrs* -tumor grade: *nottingham grade*-->tubular formation, nuclear grade, mitotic activity -tumor size, ploidy, DNA index, S phase or Ki-67 rate (marker of cell cycle activity.. aka prolif) -mets: distant 10% and nodal 20-30% (0 nodes 70-80% 10 yr DFS, 1-3 35-40%, >10 10-15%) -histologic subtype, lymphocyte invasion, receptor studies, locally advanced disease -ER and/or PR+ = better disease-free (DFS) and overall survival (OS), ~10% improvement in DFS @ 5 years for patients with ER + tumors treated with SERMS (80%+ respond, 10%- respond) -often low-intermediate histologic grade -in nucleus -HER2 overexpression indicates *poor prognosis and shortened survival* but *potential target for trastuzumab*/herceptin -correlates w/--> ER negative status, High S-phase fraction, Positive nodal status, Mutated p53, High nuclear grade -on cell surface/membrane

Rhabdomyosarcoma ~what is it (2 types) ~imaging (what does it NOT invade), histo (stain & char. cells), genetics

a soft tissue sarcoma.. can be divided into Embryonal & Alveolar RMS, can be anywhere there is muscle Embryonal RMS: ~no consistent cytogenetic abn; usually toddlers (<10), 61% of <1 yos will have this histo subgroup ~*head & neck* and *GU* Alveolar RMS: ~*extremities/retroperitoneum* ~adolescents ~*t(1;13) PAX7 FKHR* and *t(2;13) PAX3 FKHR* --> unlucky # 13.. worse prognosis imaging: does NOT invade dura histo: small round blue cell tumor of the ms, look for spindled malignant cells, freq mitoses, rhabdomyoblasts; will stain for muscle differentiation (*myogenin +* brown stain) but not for neural or hematopoeitic ~*strap cells* = striations in tumor cells, unique to RMS

Explain how the diagnosis of cancer is made and what grade and stage mean (whats the most accepted one)

almost always requires pathologic tissue diagnosis! (exception *HCC*) -serum tumor markers can suggest presence in correct clinical setting but not really used for mass screening as MC in certain benign settings, usually recurrence f/u GRADE: degree of differentiation based on microscopic evaluation of cytogenic atypia, mitosis, and architectural features-->more dysplasia/poorly differentiated = HG (usually high mitosis & more muts) STAGE: how anatomically far the tumor has spread based on size, LN, distant Mets (TNM) *most important prognostic factor*

Explain treatment of breast cancer for early stage, locally advanced, and metastatic disease

definitive therapy= excision, and regimen depends on stage and other prognostic factors -molecular tools including gene profiles (OncoDx, mammoprint) can tell you responsiveness and recurrence and are huge in breast cancer -circulating tumor cells "Early stage"- clinical stage I, IIA, subset of IIB (detected by mammos) -Surgery (lumpectomy or mastectomy), Lymph node(s) sampling, +/- radiation (based on risk of recurrence) -Adjuvant chemotherapy dependent on node status/other prognostics: ER/Her-2/positive, Large size, + LNs, HG, "High risk" of recurrence on gene panel studies -breast conserving therapy offered-->equiv recurrence/survival rate, *lumpectomy + radiation*, contraindicated w/ Multicentric disease, Large tumor, Presence of diffuse malignant-appearing calcifications on imaging, hx of chest radiation, Pregnancy, Persistently positive margins despite attempts at re-excision "locally advanced"- rest of IIB, IIIA-C -*Neoadjuvant therapy* (hormonal if receptor+ +/- chemo) -Surgery (regardless if complete clinical response): Can be mastectomy or breast conserving Metastatic at presentation (IV)- 5% of cases

being as it is the most commonly diagnosed cancer in women, what are the current guidelines for breast cancer screening?

for ave. risk woman (<20% lifetime risk, does NOT have dense breast tissue) ~ACOR/ACOG/Soc breast imaging/ACOS: annual screening mammography starting at *age 40*; continue as long as in good health, or as long as life expectancy >10yrs ~NCCN: from *25-40*, do clinical breast exam q1-3 yrs + breast awareness (pay attention to lumps, pain, skin changes, discharge); *>40* annual mamm + annual CBE + breast awareness ~other controversy bw USPSTF (every 2 yrs >50) and ACS guidelines (start at 45 w/ annual and every other at 55) for high risk woman (>20% lifetime risk... takes into account BRCA gene, hx of chest irradiation bw 10-30, syndromes, dense breasts): annual screening mammo starting age *25-30* or *10yrs before* age of 1st deg relative w breast cancer (not before 25) PLUS annual screening MRI ~also start screening 8 yrs after chest irradiation

Osteogenic Sarcoma, aka Osteosarcoma ~what is it? ~tx? (important bc new tx strategy!) ~prognosis (based on what 2 things)

~2nd MC primary malignant bone tumor (after MM) with bimodal dist (10-20 yrs old vs. >65 prob after radiation/chemo) ~RFs: pagets, Rb, li-fraumeni syndrome, previous radiation ~occurs in *metaphysis* of long bones --> MC presents as pain with mass at primary site (55% distal femur, 27% prox tibia, 11% prox humerus) ~may have pathological fx ~20% present with distant disease.. 80% of those at lung ~look for periosteal rxns (codman triangle, sunburst pattern) tx: before 1970, was dismal bc before systemic chemo, surgical resection only option; 80% of these pts died bc 50% developed mets within 6mo and 90% had recurrent disease within 2 yrs ~micrometastatic disease --> requires chemo! (*10w of neoadjuvant before surg!*) prognosis: based on *stage* & *response* ~mets only have <30% 5yr survival, localized 65-70% ~if <90% response to chemo, not good

how is radiation therapy used for breast cancer pts? which group is often offered chemo, even though it likely wont be of benefit?

~ALL breast conservation pts (lumpectomy + radiation) ~ALL pts with >4 + LNs, even after mastectomy ~ALL T4 lesions ~pts with inflammatory breast cancer (automatically T4..) ~all occult (T0, N1-2) breast cancer pts undergoing BCS *N-, ER+* = chemo probably not needed ~based on OncotypeDx assay, which determines recurrence score/RS, postmenopausal women with node-negative ER/PR+ breast cancer have survival rates at ten years with chemo that are equivalent to hormonal ablation alone ~3/4 pts (just ER+, LN- or everyone??) do not benefit from addition of chemo

what is a Wilms' tumor? ~epidemilogy ~presentation ~bx (3 things)

~MC renal malignancy of early childhood (2-4); due to LOF mut of WT1 or WT2 on chr 11 ~460 new cases per year; med age *36 mo* (Females) - *43mo* (males); M=F ~presentation (bathtub!) : asymptomatic UQ mass (doesnt cross midline), abd pain, fever, anemia, hematuria, HTN (pushes on renal a --> Renin) ~often see aniridia (no iris) or hemihypertrophy (one side of body bigger) bx: "toothpaste" ~triphasic tumor: *malig tubules, blastema, & glomeruloid structures*

what are prognositc factors for neuroblastomas? ~one of those prognostic factors is stage.. briefly describe that

~age (cutoff 18mo... <18mo localized, easier to cure) ~ploidy (diploid gonna die)--> hyperdiploid have good response to cyclophosphamide/doxo, *BUT no prognostic significance in older children* (>12mo.. >18mo?) ~shimada histology, if deemed favorable histology, do way way better ~*n-myc oncogene amplification*: >10amp signals at 2p24 is BAD ~1p, 11q LOH (loss of heterogeneity) - bad?? ~risk strat based on clinical + biologic features Stage 1 = localized tumor, complete excision Stage 2A = localized tumor *incomplete* excision Stage 2B = *LNs +* Stage 3 = *crosses midline* Stage 4 = *dissemination* 4s = localized primary tumor (stage 1-2b) with dissemination limited to skin/liver/BM (<10% of total cells malig) AND <1yo ~4S will likely go away on their own... might need to tx so they can breathe

what are the prognostic features of medulloblastomas? how do you tx based on standard risk vs. poor risk vs. infants

~extend of spread ~extent of resection (*<1.5cm residual = good*) ~age (*<3 yo* = BAD, due to radiation of growing brain) ~favorable genetics: *high TRKC* & *low ERBB2* expression standard: resection, radiotherapy (2400 cGq craniospinal axis, 5400 for tumor bed), chemo meds that penetrate BBB poor risk: higher dose radiotherapy + chemo; 50-60% LT disease control infants: radiation assoc with poor neuro-cog outcomes; chemo to delay/modify/obviate need for radiation

what is a Neuroblastoma? ~what are clinical features ~lab findings ~bx

~the MC extracranial solid tumor (500 new ones per yr) that can occur anywhere along post-ganglionic *sympathetic chain* ~60% before 2yo, 97% before age 10 ~spectrum from neuroblastoma (mostly undiff, little blue cells), to glandioneuroblastoma, to ganglioneuroma (benign/adolescents) clinical features: ~abdominal distention (MC presentation; due to predilection to start in *adrenals* 67%) ~tends to metastasize via blood (check BM!!), but also potential via lymphatics ~bone pain/pancytopenia due to BM mets ~*raccoon eyes!* (proptosis/horners & bilateral periorbital ecchymosis) ~paralysis, due to SC compression ~severe watery diarrhea due to *VIP* sec ~opsoclonus myoclonus, a central ataxia (dancing hands/feet) seen w a well-diff tumor & due to X-reactive ABs to the cerebellum Labs: *HVA & VMA* elevated in spot urine (catachol metabs); high LDH Bx: Homer-wright rosettes (25-35%), which are tumor cells arranged around central area filled with neuropill (fibrillary material composed of tangled mass of neurites)

what is the ddx for a belly mass in kids? also, unrelated, what are two things to remember about solid tumors in kids?

~wilms tumor ~neuroblastoma ~malig lymphoma ~non-malig.... meckels, appendicitis, cystic kidney solid tumors: ~dont do FNA! & get fresh tissue ~tumor lysis syndrome can still happen!