Pathology Week 6 p18-35

7/30/2019 Pathology Week 6 p18-35

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Result of QA Procedures:- 2009: 23% GYN cases re-screened- 62 Negative cases reclassified: ASC-US+

Epithelial Cell Abnormalities: Squamous Cell- Atypical squamous cells, of undetermined

significance (ASC-US)- Atypical squamous cell, cannot exclude HSIL

(ASC-H)

ASCUS: Cytologyic Follow-Up- 643 Study patients- 137 SIL on cytology follow-up (11.7%)- 46 HSIL on cytology follow-up (6.0%)

ASCUS Follow-Up Literature Review: BiopsyImmediately Following ASCUS Daignosis:

- 15 studies, 3414 patients- 36% SIL rate (range, 16-60%)- 12% HSIL rate (range, 4-25%)

ASCUS Follow-Up Conclusions:- Among ASCUS patients followed for up to 9

years, 20% develop only low grade SIL or milddysplasia and 10% develop HSIL or moderate orsevere dysplasia

- ASCUS should be retained as a diagnosticcategory since it identifies a significantpercentage of patients who are at an increasedrisk for the development of cervical dysplasia.

Age of DNA Testing:- The sensitivity of HPV DNA testing for the

detection of biopsy-confirmed CIN 2,3, in womenw/ASCUS is 83%-100% and is higher than thesensitivity or a single repeat cytologic test.

- Between 31% and 60% of all patients w/ASCUSwill have high riskHPV types.

Case: 37F;Conventional smear:

Cytologic Diagnosis: Adenocarcinoma in situ (AIS).

Cervical Cone Biopsy:

Histologic Diagnosis:- Invasive

endocervicaladenocarcinoma

- 5mm depth

- 9mm width- Close to margins

(.1mm)


2/18

Case: 73F; Postmenopausal bleeding; Conventional smear:

Final Histologic Diagnosis: Endometrial adenocarcinoma.- Clear cell adenocarcinoma- 1.0cm- FIGO grade 3/3- Invasion into superficial half of myometrium

ThinPrep AGC Follow-Up Study:- AGC diagnosis ignored in 41%- 32% of HP Dx significant- 95% >35

- 17 malignancies- All malignancies in older age group- 15 endometrial primary- 2 metastases

Points to Remember:- Lab test does not replace careful clinical exam- Must perform colposcopy and biopsy cervical

lesions

- Biopsy suspicious cervical lesions- Colposcopy may miss endocervical lesions

Bronchogenic Carcinoma:- #1 cancer in US accounts for greatest number

of cancer deaths- 80% of all cancers can be diagnosed

preoperatively by cytology- minimum of false positives

Respiratory Tract Cytology Indications: All patientssuspected of harboring a primary or secondarypulmonary malignancy

Benign conditions:- Asthma- Asbestosis- CMID- PCP

Sputum Cytology Results:- sputum detection rate- single sputum detection rate = 30%- better forcentral tumors- better forprimary tumors- false positive rate


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Effusion Cytology:- pleural fluid- peritoneal fluid- pericardial fluid- serous membranes:

- lined by flattened mesothelium- underlying connective yissue- lymphatics- blood vessels

Pleural Fluids:- CHF 12%- infection 22%- unknown 10%- pulmonary embolus 3%- cirrhosis 2%- most common neoplasms: breast, lung- most common infection: TB

Ascitic Fluid- cirrhosis- CHF- malignancy- most common source of primary, male: GIT

- most common source of primary, female: FGTPericardial Fluid:

- 1% of effusion specimens- exudates > transudates- % malignant = 27.6- most metastases:

- breast 33%- lung 20%- colon 20%- lymphoma 7%

Urinary Cytology Indications:- suspected bladder, ureteral, or renal pelvis

cancer- history of treated TCC- persistent symptoms of bladder irritation- occupational history- suspected renal adenocarcinoma

Urinary Cytology Types of Specimens:- voided urine good (hydrate patient)- bladder wash good- cytoscopic urine good- first AM urine no good- catherterized urine no good- lavage not always better than voided urine

Other Sites Amenable to Cytologic Evaluation: GIT,CSF, oral cavity, larynx, nasopharynx/paranasal sinuses,eye.

GIT:All areas accessible to brushing, washing, aspiration- biliary tree- pancreatic duct- esophagus

Regenerating cells near ulcers can cause diagnosticconfusion.Japan: screened 200,000 gastric cancers, detected lowstage.

CSF:- lumbar or cisternal puncture- send to lab immediately- If lab closed: refrigerate, add equal volume

balanced salt solution + 20% albumin

Fine Needle Aspiration (FNA) Cytology:- Superficial (palpable) masses- Deep-seated lesions

FNA Cytology Requirements:- Cytopathologist- Properly trained radiologist- team approach- as much clinical data as possible

FNA Cytology Value:- definitive diagnosis- documentation of metastases- evacuation of cysts- triage

FNA Advantages:

- relatively atraumatic- accurate- rapid- cost-effective

FNA Cytology Cytomorphologic Evaluation:- nucleus- cytoplasm- entire cell- intercellular relationships- smear background

(video on fine needle aspiration cytology)

Entities Diagnosable by FNA Cytology of Superficial(Palpable) Lesions Partial List

Breast- infiltrating duct carcinoma- intraductal carcinoma- medullary carcinoma- fibroadenoma- cystosarcoma phylloides- fibrocystic disease- gynecomastia- mastitis (acute/chronic)

Lymph Node- metastatic carcinoma- metastatic melanoma- malignant lymphoma- Hodgkins disease- reactive lymphoid hyperplasia

Salivary Gland- pleomorphic adenoma- Warthins tumor- adenoid cystic carcinoma- mucoepidermoid carcinoma- chronic sialadenitis


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Thyroid Gland- papillary carcinoma- follicular lesion- Hurthle cell lesion- nodular goitre- Hashimotos thyroiditis- lymphocytic thyroiditis- malignant lymphoma

Soft Tissue- metastatic carcinoma- metastatic melanoma- benign fibroblastic lesion- malignant fibrous histiocytoma- leiomyomal/leiomyosarcoma- lipomal/liposarcoma- sarcoma, not otherwise specified

Lung- all varieties of carcinoma- mesothelioma- pulmonary hamartoma- malignant lymphoma- inflammatory/infectious diseases

Pleura

- adenocarcinoma- mesothelioma

Mediastinum- thymoma- malignant lymphoma- germ cell tumors

Liver- hepatocellular carcinoma- leiomyosarcoma- angiosarcoma/hemangioma- abscess

Pancreas- pancreatic carcinoma

- islet cell tumor- chronic pancreatitis

Kidney- renal cell carcinoma- transitional cell carcinoma- angiomyolipoma- oncocytoma

Adrenal- adrenal cortical adenoma- adrenal cortical carcinoma- pheochromocytoma

Retroperitoneum- malignant lymphoma- sarcoma

Deep Seated Lesions- fluoroscopy- ultrasound- CT- endoscopic FNA

Ancillary Studies- Electron microscopy- Immunoperoxidase staining: direct smears,

cytospin preparations

- Flow cytometry: cell surface marker analysis,DNA analysis

FNA Complications (11,700 patients)- mortality rate 0.008%- total complication rate 0.55%- major complication rate 0.05%- minor complication rate 0.49%- Major complications: biliary peritonitis (2), tumor

seeding (1), intrahepatic hematoma (1),peritonitis (1)

- Other complications: needle tract implantation(papillary ca, thyroid), needle tract seeding

(pancreatic ca), cutaneous seeding (pancreaticca), necrosis (Hurthle cell tumor), acute thyroid

swelling, massive bleeding (liver)


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Pathology of Breast Fri. 09/24/10

Signs & Symptoms: Mass/lump

Fibrocystic disease Fat necrosis will see giant cells and foamy

macrophages. Fibroadenoma and related lesions Carcinoma

Nipple discharge ?bloody (Non-bloody = benign) Papilloma Carcinoma

Mammographic abnormality Microcalcifications

Fibrocystic disease Carcinoma, particularly DCIS

Architectural distortion Fibrocystic disease Carcinoma, particularly lobular

Normal breast: fat + breast tissue Ducts Terminal ducts lobular units (TDLUs)

Lined by 2 layers of cells Epithelial (luminal) Myoepithelial (basal) - surrounded by a basement membrane

Benign diseases have both cells types Malignant lesions have only one.

Fibrocystic changes: Terminology--fibrocystic changes, fibrocystic disease, chronic cystic mastitis,periductal mastitis, mammary dysplasia, cystic mastalgia Three dominant morphologic patterns

Cystic formation and fibrosis Epithelial hyperplasia

Sclerosing adenosis Demographics

Microscopically extremely common, present to some degree in 60 to90% of breasts in routine autopsies

Everyone has fibrocystic change to some extent Etiology: Variable end-organ response to hormonal stimuli Cysts and fibrosis

Mass and or Microcalcifications (phosphate) Unopened cysts are brown to blue (blue-dome cysts) Very common type - characterized by an increase in

fibrous stroma associated with dilatation of ducts andformation of cysts of various sizes.

Gross cysts > than 3 mm, micro cysts smaller

Cysts often lined by large polygonal cells with abundanteosinophilic cytoplasm--so called apocrine metaplasia.Cuboidal epithelial cells.

Fibrocystic disease: sclerosing adenosis w/calcificationArrow shows a focus of microcalcification.

Test q:A 27y/o woman feels a lump in her right breast. She has normal

menstrual cycles, she is G3, P3, and her last child was born 5yr ago. Thephysician palpates a 2cm, irregular, firm area beneath the lateral edge of theareola. The mass is not painful and does not feel firm. There are no lesions of

the overlying skin and no axillary lymphadenopathy. A biopsy specimen showsmicroscopic evidence of an increased number of ducts, which are compressedbecause of proliferation of fibrous connective tissue. Dilated ducts w/apocrine

metaplasia also are present. What is the most likely diagnosis? Fibrocystic disease

Above: normal breast. Myoepitheliallayer periphery, between epitheliallayer and basement membrane.

Test q:A 40y/o woman who was recently in an automobile accident noticeda firm mass in the upper-outer quadrant of her right breast. A mammogram

2mo ago was normal. Which microscopic description is most consistentw/the clinical history? Giant cell and foamy macrophages.

Test q:A 30y/o woman sustained a traumatic blow to her right breast.Initially, there was a 3cm contusion that resolved within 3wk, but she thenfelt a firm lump that persisted below the site of the bruise 1mo later. What is

the most likely diagnosis for this lump? Fat necrosis

Test q:A 36y/o woman has noticed a bloody discharge from the nipple ofher right breast for the past 3 days. On phys exam, the skin of the breastsappears normal, and no masses are palpable. There is no axillarylymphadenopathy. The patient has regular menstrual cycles and is using

oral contraceptives. Excisional biopsy is most likely to show which of thefollowing lesions in her right breast? Intraductal papilloma

Test q: Histologic features seen in breast ducts that are worrisome forbreast cancer are: cell uniformity and microcalcification


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Portions of cytoplasm are chewed off. Usually always benign.Apocrine metaplasia no longer have apocrine secretion.

Fibrocystic changes: Epithelial hyperplasia

(a little worse than cyst formation)

commonly coexists with fibrosis, cysts, adenosis Microscopically, proliferation causes an increase

in the layers of the duct-lining epithelium beyondthe usual double layer

Mild, moderate or florid The presence of architectural and/or cellular

atypia warrants a diagnosis of atypicalhyperplasia

Figure: Duct lobular units filled w/a number of cells polyclonal in origin. Lumen is irregular. Normal becauseits association w/malignancy is not strong.

Sclerosing adenosis destruction of normal lobular architecture.Increased number of glands. Sclerosis = fibrosis; Adenosis = # of glands Clinical- hard cartilaginous consistency that begins toapproximate that found in breast cancer. Microcalcifications frequent Proliferation of both epithelial and myoepithelial cells Minimal or no increased risk for cancer.

Figure: sclerosing adenosisGlands are not clear. Increased numberof epithelial cells. Sclerosing adenosis is

associated w/calcifications.

Clinical significance of fibrocystic changes: Produce lesions mimicking carcinoma

the following features favor benign disease: bilaterality, multiple nodules, pain prior to menstruation, type ofmicrocalcifications

Some histologic types may predispose or are a marker for the subsequent development of carcinoma especially those with epithelial hyperplasia

(Proliferative and non-proliferative types)


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Types of fibrocystic change and risk of subsequent carcinoma: No increased risk: fibrosis, cystic changes, apocrine metaplasia, sclerosing adenosis, mild hyperplasia Slightly increased risk, 1.5 to 2 times: hyperplasia moderate to florid, ductal papillomatosis Significantly increased risk, 5 times: atypical hyperplasia, ductal or lobular with ductal involvement. A family history of breast cancer increase the risk in all categoriese.g., to about 10-fold with atypical

hyperplasia. DCIS = 10x risk

Test q: The change within the spectrum of fibrocystic disease that is associated w/the greatest risks for breast cancer is: atypical hyperplasia

Breast carcinoma

Breast carcinoma causes some 20% of cancer deaths among females. 43,000 deaths in US Age adjusted death rate about 27 per 100,000 1 of 11 women in US have a lifetime risk for developing the disease (incidence)

Breast carcinoma: Incidence and epidemiology: Geographic influences: 5 times more common in US than Japan and Taiwan Genetic predisposition: Well defined. The magnitude of risk is in proportion to number of close relatives with breast

cancer and age when cancer occurred in relatives. The younger the age of relatives and more bilateral cancers thegreater the genetic predisposition. Uncommon families with apparent autosomal dominant transmission and familialassociation of breast and ovarian carcinomas.

Increasing age: Uncommon before age 20, but then a steady rise to the time of menopause, followed by a slower risethroughout life

Length of reproductive life: risk increases with early menarche and late menopause (exposure of breast to increasedestrogens)

Parity: More frequent in nulliparous than in multiparous women Age at first child: Increase risk when over 30

Early pregnancy (full-term, not abortion) is protective Obesity: Increased risk attributed to synthesis of estrogens in fat depots Exogenous estrogens: Still controversial Oral contraceptives/Abortion: No clear-cut increased risk Fibrocystic changes with atypical epithelial hyperplasia: increased risk Carcinoma of the contralateral breast or endometrium: increased risk Diet and environmental agents: high lipid diet and moderate alcohol consumption increase risk slightly (only w/alcohol

and NO folate)

Familial Breast Cancer: BRCA1 more aggressive tumors

Younger women, high grade tumors, ER- BRCA2 no specific association

Relatively older, low grade (lobular) tumors BRCA1 and 2 common in Ashkenazi Jews. Involve DNA repair and scaffolding. Others

p53, Chk2, ATM, pTEN do not know significance unknown

Carcinoma in-situ (pre-disposing) Types of ductal carcinoma in-situ (DCIS):

Based on ARCHITECTURE (old) not used muchanymore.

Solid Comedo necrosis On cut section central necrosis leads to easily

extruded by slight pressure giving rise the termcomedocarcinoma

Cribriform Papillary Micropapillary Usual variants: Apocrine, Clinging, Clear cell

Some have all of the above, so we use nuclear grade.Better to diagnose w/this.

Based on NUCLEAR GRADE constant in any lesion. Low Intermediate High

Above: Duct filled w/monotonous population ofcells, can also have foci of calcifications.

Test q: Genes known to have

mutations responsible fordevelopment of breast neoplasmsinclude all the following EXCEPT:

Abl (Other choices: BRCA1, P53,Heu/2, BRCA2)


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Above: Cribriform c-shaped. Ducts in a duct. Above: Comedo name comes from zit. When yousqueeze it, pus comes out.

Test q:A 63y/o woman feels a small lump in her right breast. The physician palpates a firm area that has a cordlike feel. No lesions of the overlyingskin are present, and there is no axillary lymphadenopathy. A mammogram shows a density that contains microcalcifications. An excisional biopsyspecimen contains soft, white material that is extruded from small ducts when pressure is applied. Microscopic exam shows ducts that contain large,

atypical cells in a cribriform pattern. What is the most likely diagnosis? Comedocarcinoma

Lobular carcinoma in situ:

proliferation in terminal ducts and/or ductules ofloosely cohesive cells

risk factor for the subsequent development of eitherinfiltrating ductal or lobular carcinoma, 9x risk

- Not invasive, but associated with risk.

Pagets Disease: carcinoma cells going through ductalsystem and involving epidermis. Specialized form of ductal carcinoma that arises in the

main excretory ducts of the breast and extends toinvolve the skin of the nipple and areola.

Clinically, eczematoid changes occur in the nipple and areola(scaling and erythema)

Ductal carcinoma, with or without invasion, invariablyantedates the skin change.

30 to 40% of women have metastases at the time of surgery Histologic hallmark of this entity is the involvement of the

epidermis by malignant cells, referred to as Paget cells

Test q: Pagets disease of nipple is associated with: Invasive ductal carcinoma

Invasive Breast carcinoma: Clinical presentation Mass Mammaographic abnormality

Microcalcifications Architectural distortion

Nipple symptoms Inversion or discharge

Approximately 50% arise in the upper outer quadrant; 10% in theremaining quadrants and 20% in the subareolar region

Test q: The most common location for ductal carcinoma in the breast is: Upper-Outer quadrant

Advanced or untreated cases: Lympho-hematogenous spread tumor spreads through lymphatics. Stage IV.

axillary and internal mammary lymph nodes Distant metastases usually to l iver, lung, and bone. Brain metastases = lethal.

Adherent to the chest wall extension to the skin (retraction and dimpling)

Above: Pagets disease of the nipple. Local

involvement of the skin. Tumor cells = lightly colored.Dermis is free of tumor. Tumor infiltrating to epidermisbut is NOT an invasive cancer.

Figure: LCISMonotonous cells

lack ofpleomorphisms.

See spaces

without cells.Ducts filled withsolid masses of

cells.


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dermal lymphatic involvement leads to skin thickening and lymphedema, peau dorange (orange peel)

Acute swelling, redness, and tenderness. Inflammatory carcinoma poorprognosis.

Classification: Molecular/Intrinsic

ER positive (luminal) ER negative

Her-2 positive Basal type Histological

Ductal 90% of cancers Lobular do not make glands, Indian-filing. Bilateral, high-stage (not detected).

Intrinsic classification: cDNA based 100s of cases ?Anatomic not sure if

anatomic is thought to beprognostic.

Also prognostic

ER + = luminal AER - = other luminals

Luminal A = low grade tumor.

Intrinsic Subtype Classifier: SignificantPrognostic Information Luminal A pts had best OS & RFS betterprognosis. Basal type patients had the worst HER2 patients had an intermediate

Luminal B, though ER+, did significantly worse thanLuminal A

Infiltrating ductal carcinoma: Grossly has a hard cartilaginous consistency and produces a grating soundwhen scraped. Dense fibrous stroma gives rise to the tumor a hardconsistency and thus have been called scirrhous carcinoma Grading (Scarff-Bloom-Richardson) Nottingham.

Tubule formation more = better Nuclear grade less = better (nuclear polymorphism) Mitotic activity less = better

Based on these parameters graded as I, II or III

Figure: Infiltrating carcinomaBreast cancer use ink to see

where the tumor is.Note stellate shape.

Figure: infiltratingductual carcinoma

Low grade tumor associatedw/tubule formation.

Desmoplastic stroma = scar.

Note duct-like structures anddesmoplastic stroma.

Variants of ductal carcinoma: Good prognosis Tubular carcinoma Mucinous carcinoma Medullary carcinoma Adenoid cystic carcinoma Bad Prognosis Metaplastic carcinoma squamous cell carcinoma Carcinoma with osteoclast-l ike

giant cells Apocrine carcinoma

Test q: Inflammatory carcinomas of thebreast exhibit: lymphatic invasion by

tumor

Test q: The left breast of a 39y/o female

is slightly enlarged compared w/the right.The skin overlying this breast isthickened, reddish-orange, and pitted.

Mammography reveals a 3cm underlyingdensity. A fine-needle aspirate of thismass reveals carcinoma. How is the

gross appearance of the left breast bestexplained? Lymphatic obstruction.


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Test q: Which of the following breast cancers has the WORST prognosis? Invasive ductal carcinoma (Other choices: tubular carcinoma, medullary

carcinoma, mucinous (colloid) carcinoma, and fibroadenoma. See good prognosis list above.)

Tubular carcinoma: Tubular carcinoma: Low SBR grade

Typically grade I Good prognosis LN mets uncommon Systemic mets very rare

Colloid or mucinous (extracellular mucin) carcinoma: This variant of ductal carcinoma tends to occur in older women and

grows slowly over years. Grossly the tumor is extremely soft and the consistency and

appearance of pale gray-blue gelatin Histologically, tumors is composed of large pools of extracellular

mucin that dissects and extends into contiguous tissue spaces andplanes of cleavage. Floating within this mucin are small islands andisolated neoplastic cells, sometimes forming glands.

Tumors may be mixed and composed of mucinous and non-mucinous (typical ductal) elements

Survival rate is greater in pure colloid carcinoma than in the usualtype infiltrating duct carcinoma and lymph node metastases areinfrequent

Invasive lobular carcinoma (Think INDIAN FILING) WHO definition composed ofuniform cells resembling those of

lobular carcinoma in situ and usually having a low mitotic rate. The cells grow typically in a single-file, linear arrangement, or

appear individually embedded in fibrous tissue. Targetoid growthpattern and identification of remnants of lobular carcinoma in situaid in the diagnosis.

Signet-ring cells may be seen not associated w/a bad prognosis.

Clinical features of lobular carcinoma:

Lobular carcinoma comprises 3 to 14% of invasive carcinomasdepending on the criteria involved

Grossly, mass is rubbery with ill-defined margins Not prone to form calcifications Relatively high frequency of bilateral & multicentric carcinoma--6

to 28% prior or concurrent contralateral carcinoma

Pathologic features of lobular carcinoma: Firm, rubbery to hard tumor with irregular borders, though may not

be visibly abnormal or only slightly firm to palpation Microscopic findings the infi ltrating portions of lobular carcinoma

typically reveal thread-like strands of tumor cells rather looselydispersed through out a fibrous stroma.

So-called Indian-file pattern and targetoid growth patterns-- thelatter is represented by concentric rings about normal ducts

Small or medium-sized cells exhibiting relatively little nuclearirregularity.

Central mucoid globules helpful diagnostic feature.

Figure: Nuclear pleomorphismand mitotic activity is minimal.

100% of tumor is forming glands.

Above: mucinous carcinoma. A lot of mucin,so bigger and diagnosed early.

INDIAN FILING


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TNM Staging clinical

T-Primary tumor based on size T1: 2cm 5 cm

T4: any size with extension to skin/chest wall N-Regional lymph nodes

NX: regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis to movable ipsilateral axillary nodes(s)

N2: Metastasis to ipsilateral axil lary node(s) fixed to oneanother or to other structures

N3: Metastasis to ipsilateral internal mammary lymph nodes M - Distant metastasis

MX: Presence of distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis ( includes metastasis to

supraclavicular lymph nodes

Prognosis for invasive Breast carcinoma:10-year disease free survival

80% for T1N0 90% for T1N0 < 1 cm.

70% for T2N0 60% for T3N0

Prognostic Factors:

Tumor Size: small tumors -favorable prognosis

Lymph node involvement- 2/3rds have LN mets at the

time of initial diagnosis 5 year survival.

nearly 80% with no nodalinvolvement 20 to 30% with negative

nodes recur and die ofdisease within 10 years

50% with 1 to 3 nodes involved 21% with 4 or more nodes

involved Histological Grade

Lymphatic or Blood vesselinvasion

Increase proliferative rate thymidine and

bromodeoxyuridinelabeling

flow cytometry-S-phasefraction

Ki-67, PCNA (proliferatingcell nuclear antigen, aka-

cyclin)

Estrogen andprogesterone receptors

therapeutic targets 70% of tumors with

positive ER regressafter hormonalmanipulation, whereasonly 5% that arenegative respond to

these procedures Tamoxifen binds

and inactivatesestrogen receptors.

Her-2/neu (cerb B2)amplification

Herceptin treatmentthat interferes w/theHer2/neu receptor

Sarcomas of breast Fibrosarcoma and malignant fibrous histocytoma

Liposarcoma Osteosarcoma and chondrosarcoma

Postirradiation sarcoma Hemangiopericytoma Angiosarcoma

Post mastectomy angiosarcoma (Stewart-Trevessyndrome)

Mixed Epithelial and Stromal tumors: Fibroadenoma fibrous tissue and glandular tissue; in young

women. Benign

Glandular and stromal elements Does not undergo malignant change

Phyllodes tumor glandular and stromal More cellular stroma than FA Cellular pleomorphism, necrosis May be benign or malignant

Benign morphology is poor predictor of behavior

Test q:A 38y/o female has a left breast lumpectomy. Amass which measures cm in greatest diameter is excised

as are two sentinel lymph nodes from the left axilla. Thetumor consists of well-formed glands (tubules), exhibits nomitoses and has no nucleoli. The ductal adenocarcinoma is

focally invasive and there is minimal desmoplasia. Bothlymph nodes are negative for adenocarcinoma and there isno evidence of distant metastases in liver, lung, or bone.

Special stains for Estrogen Receptor (ER) and Her-2 Neu aretotally negative.

- The grade of this tumor is: I

- The stage of this tumor is: T1N0M0- The treatment plan for this patient will include:neither tamoxifen nor herceptin

Test q:A mass is biopsied from the lef t breast of a 42y/ofemale. Invasive ductal carcinoma is present. All tumor cells

are present as round glands. Mitoses are not seen andnucleoli are absent. This tumor can be described as: lowgrade. (Other choices: anaplastic, undifferentiated,

hamartoma, or CIS) The tumor measures 1.1cm in diameter.Three sentinel lymph nodes are all negative for tumor.Distant metastases are not detected. The stage of this

neoplasm is: T1N0M0

Test q:A 50y/o woman saw her physician af ter noticing a

mass in the right breast. Physical exam showed a 2cm massfixed to the underlying tissues and three firm, nontender,

lymph nodes palpable in the right axilla. There was no familyhistory of cancer. An excisional breast biopsy wasperformed, and microscopic exam showed a well-differentiated ductal carcinoma. Over the next 6mo,

additional lymph nodes became enlarged, and CT scansshowed nodules in the lung, liver and brain. The patient died9mo after diagnosis. Which of the following molecular

abnormalities is most likely to be found in this setting?Amplification of the c-erb B2 (HER2) gene in breastcancer cells REPEATED x5!! (Once, answer was

Amplification of the ERBB2 (HER2) gene)

Test q:A mass was removed from the breast of a 46y/o

female. The surgery performed was a lumpectomy w/axillarytail dissection (to look for metastatic disease in lymph nodes).The tumor measured 5.4cm in greatest diameter. Stromal

invasion was extensive and desmoplasia was identified. 3-4mitoses were present in every high-power field. Gland/tubuleformation was not present and most of the tumor showed

sheets and nests of undifferentiated malignant cellsw/prominent nucleoli and irregular chromatin clumping. 15lymph nodes were harvested from the axillary tail and 6/15

were positive for adenocarcinoma. 3 of the positive nodeswere matted together and fixed (surrounded by fibrosis) to thesurrounding soft tissue. Staining for estrogen receptors wasentirely negative. Staining for Her2-Neu showed strongly

positive cytoplasmic and membrane staining in 90% of thetumor cells. There was no clinical evidence of distantmetastases.

- An accurate grade for this tumor would be: Bloom andRichardson Grade III.- Additional treatment for this patient would include:

Herceptin.


12/18

Fibroadenoma:

Above: Can see circumscribed, firm white area in the fibroadenoma. Above: FA-cellular view is a bit more fibrous, but not

enough to be Phyllodes.

Phyllodes:

Above: Malignant Phyllodes. Stromal part = increased cellularity. Can havemitotic activity, pleomorphism, etc.

CONFERENCE: Tumor Invasion and Metastasis Fri. 09/24/10

Neoplasms:Benign MalignantNon-invasive InvasiveNon-metastatic Metastatic or non-metastatic

Exceptions to the RuleBenign tumors that may kill the patient:

- Meningioma: expand, compress brain- Leiomyoma: do not mestastasize but expand

leiomyoma can erode blood vesselsMalignant tumors without metastasis:

- Glioblastomamultiforme- Basal cell carcinoma

Malignant Tumor Properties- Penetration of the basement membrane- Invasion and destruction of surrounding tissue- Penetrate organ walls or fungate through the surface- Local invasion, like metastasis is a marker for malignancy- See Robbins Table 7-2 for benign vs malignant features

Bottom line in breastlesions: IS IT BENIGNOR MALIGNANT?

Benign: Smaller and well-circumscribedMalignant: spindle/irregular border


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Metastasis- #1 marker of malignancy- Exceptions: gliomas

(astrocytomas) of the brainand basal cell carcinomas ofthe skin RARELYmetastasize; also,meningiomas LOCALLYinvade skull bone, but do notmetastasize and areconsidered benign.

- (No lymphatics in the brain)- ** On board exams they

sometimes substitute

invasiveness for metastasis

Cancer Statistics:

- 90% of cancer deaths are due to metastases- 1/3 of breast and colon cancer patients have

lymph node metastases at diagnosis- Frequency overall: liver, lung, bone (most

frequent sites of metastasis)- #1 endocrine site: adrenal glands

Test q: The #1 cause of death in cancer patients is: Metastasis

Stage of tumors at diagnosis, listed by organ/site:

Pathways of Spread- Direct seeding of body cavities: peritoneal #1; also pleural,

pericardial, subarachnoid, joint- Lymphatic spread: carcinoma> sarcoma; follows natural

drainage- breast cancer (Upper-Outer Quadrant) goes 1st

toaxillary nodes

- Hematogenous spread (through blood): esp. sarcoma; alsocarcinoma; usually veins

- Other: eg. Perineural spread tumors can grow along the nerve

Venous Drainage- Portal: liver- Caval: lungs- Paravertebral plexus: bypasses liver and lungs. Thyroid and

prostate carcinomas metastasize to the vertebrae- Renal Cell CA: grows right along the bein. Invades renal vein and

grows into the vena cava

Above: Malignant breast tissue. Cansee irregular fingers sticking out. Notwell circumscribed.

Above: glioblastoma, highest grade. Do notmetastasize, kills by expansion into brain tissue

Figure: Metastatic melanomaMost malignant brain tumors are

metastases from other sites.

Above: subarachnoid spread in brain.

Above: Breast cancer. Everything around nerve(pink) = glands growing in perineural space.


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Sentinel LN Biopsy- The first node in a regional lymphatic basin that receives lymph flow

from the primary tumor. If free of disease, do not remove more.- Dyes and radiolabeled tracers mark the node- Breast, colon and melanomas- In breast carcinomas it replaces a total dissection of the axillary lymph

nodes and reduces morbidity (decreased risk for edema andangiosarcoma)

Test q:A 58y/o woman diagnosed w/breast cancer in the left breast underwent a

mastectomy w/axillary lymph node dissection. Postoperatively, she developed markedswelling of the left arm that has persisted for several months. The left arm is not tender or

erythematous, and it is not painful to movement or touch. What alternative procedure mighthave prevented this complication? Sentinel lymph node biopsy.

ANGIOGENESIS- Tumors stimulate the growth of host blood vessels- Any tumor >2 mm in diameter must have a vascular supply- New vessels supply oxygen and nutrients and endothelial cells secrete growth factors

Tumor Blood Vessels- Sprout new capillaries or recruit host endothelial cells- Tumor vessels are irregular and leaky due to high levels of VEGF- Tumor cells can also mimic endothelial cells (vasculogenic mimicry)

Tumor-associated Angiogenic Factors:- VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) are made mostly by tumor cells

but also by macrophages and stromal cells

ANGIOGENIC SWITCH:- Angiogenesis is delayed; a minority of the cells become angiogenic- p53 inhibits angiogenesis by inducing production of thrombospondin-1 and down-regulating VEGF- Angiogenesis inhibitors made by tumor cells: thrombospondin-1; and angiostatin (from plasminogen),

endostatin/tumstatin (collagen)- All are possible therapeutic targets!

Test q: Which of the following situations favors tumor angiogenesis? Homozygous deletion of p53

Invasion and Metastasis:- Robbins Figure 7-42

- Cells break loose, enter and exit vessels and establish a 2 growth site

- Rare malignant cells are successful at metastasis; Robbins Figure 7-43

Steps in Metastasis: Detachment of cells from the

primary tumor Invasion of the surrounding

tissue Penetration to blood and

lymphatic vessels Arrest at target sites

Egression (extravasation) Proliferation Establishment of a new blood

supply and tumor

Metastatic Cascade


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Invasion of the Extracellular Matrix (ECM)- Basement membrane- Interstitial connective tissue- Vessel basement membrane- Vessel basement membrane- Interstitial connective tissue

Steps in the Invasion:- Detachment of cells (E-cadherin/catenins)- Attachment to the ECM (integrins attach to laminin/fibronectin)- Degradation of the ECM type IV collagen by serine, cysteine

and matrix METALLOPROTEINASES (MMPs)- Migration of tumor cells (chemotaxis due to MMP cleavage

products- growth factors released also- MMPs need zinc to function.- Integrins on the tumor cells, attach to laminin and

fibronectin.

Test q:A 61y/o woman has felt a lump in her breast for the past 2mo. On phys exam, there is a firm 2cm mass in the right breast. An excisional biopsyspecimen of the mass shows carcinoma. Immunoperoxidase stains for matrix metalloproteinase-9 are performed on the microscopic tissue section

and show pronounced cytoplasmic staining in the tumor cells. Which of the following characteristics is most likely to be predicted by this marker?Invasiveness.

Tumor Cells in Circulation:- They clump with each other, RBCs and platelets

- Adhesion to endothelium (integrins-laminin-proteinases) reattachment

Test q:A 48y/o woman notices a lump in her left breast. On phys exam, the physician palpates a firm, non-movable, 2-cm mass in the upper outerquadrant of the left breast. There are enlarged, firm, nontender lymph nodes in the left axilla. A fine-needle aspiration biopsy is performed, and the cells

present are consistent w/carcinoma. A mastectomy w/axillary lymph node dissection is performed, and carcinoma is present in two of eight axillarynodes. Which of the following factors is most likely responsible for the lymph node metastases? Increased laminin receptors on tumor cellsREPEATED x2

Tumor Tropism- Different endothelial receptors in different organs- Different chemokine receptors on the tumor cells- eg. breast cancers express CXCR4 and CCR7 receptors and

matching chemokines are at high levels in lung and lymph nodes. Chemokines influence where tumors willmetastasize.

- unfertile soil like skeletal muscle without receptors

Catenin attach tocadherin.

Under expression ofcadherins, more likely tometastasize.

Cadherins cellattachment.

Leads to breakdown ofthe matrix.


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Tumors exit blood vessels due to chemokine andchemokine receptor matches:

Metastasis Genes:- Ezrin: a membrane component required for metastasis in

osteosarcoma and rhabdomyosarcoma- Anti-metastasis genes: NM23

Test q:A 48y/o woman notices a lump in her left breast. On phys exam, the physician palpates a firm, non-movable, 2cm mass in the upper outerquadrant of the left breast. There are enlarged, firm, nontender lymph nodes in the left axilla. A fine-needle aspiration biopsy is performed, and the cellpresent are consistent w/carcinoma. A mastectomy w/axillary lymph node dissection is performed, and carcinoma is present in two of eight axillarynodes. Which of the following factors is most likely responsible for the lymph node metastases? Overexpression of Ezrin in tumor cells.

Metastasis Oncogenes- SNAIL and TWIST (breast cancer)- Epithelial-to-mesenchymal transition- E-cadherin is down-regulated and vimentin is up-regulated

Targeted Therapy: Signal-transduction Inhibitors- Block enzymes and Growth Factor Receptors- GLEEVEC (imatinib)- GIST (GI stromal tumor) and CML (abnormal

tumor enzymes);- IRESSA (gefetinib)- non-small-cell lung cancer (EGFR)

Drugs designed to attackrapidly diving cells

Now trying to developtargeted drugs

Above: Tumor disappearance w/targeted therapy drug.

Metastases and Tropism:

Primary Site and Histology Organ- Clear cell carcinoma (kidney) Thyroid- Cutaneous melanoma Small bowel/brain- Ocular melanoma Liver- Adenocarcinomas Ovary (Kruckenberg

of the GI tract tumor)- Follicular carcinoma, thyroid Bone

Above: Ezrin. With this gene, tumors can metastasize.

Figure: Gleevec.Prevents phosphorylationof enzymes in tumors.


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Target:Apoptosis Inducers- VELCADE- multiple myeloma (blocks proteasomes)- GENASENSE- leukemias and lymphomas (blocks

BCL-2 restores apoptosis)- Bad to have low levels of normal p53 or high

levels of abnormal p53.

Target: Monoclonal Antibodies- Herceptin invasive breast carcinomas (that show

overexpression of HER-2-neu). Antibody againstreceptor.

Target: Anti-angiogenesis drugs have not beeneffective in humans.- Angiostatin (from plasminogen)- Endostatin (from collagen)

Figure: Tumor lining

more leaky, more TNF- receptors,

another possible drug target.

Pathology C603 Block I Review Mon. and Tues. 09/27-09/28

Most of the inflammatory cells in this photo are:

A. EosinophilsB. LymphocytesC. MacrophagesD. NeutrophilsE. Plasma cells

Abscesses are associated w/neutrophils.

Answer: D, neutrophilsThe gross is a brain abscess and the microscopic shows asheet of neutrophils. Some cells show 3 lobes while others show 1 or 2. Remember, you are looking at a 2-dimensionalimage, so you cannot identify every cell.

TYPES OF NECROSIS:COAGULATIVE InfarctsLIQUIFACTIVE AbscessCASEATION TB GranulomaFAT (ENZYMIC) Pancreas and Breast

Fat necrosis in pancreas due to release oflipases and enzymes by the acinar glands.Fat necrosis in breast sheets ofmacrophages, no enzymes involved.

Above: granuloma see giant cells (circled).Also, rim of T cells around the edge of the granuloma.


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Above: pancreas enzymic (fat) necrosis, Above: Fat Necrosis (L) and Normal Pancreas (R)saponification. Fatty acids broken down byenzymes soap

Fibrous vs Fibrinous:Fibrosis/fibrous Fibrinous

- Fibroblasts/collagen Fibrin/liquid protein- Scar, desmoplasia, sclerosis Pericarditis and peritonitis- Permanent Reversible, but may become fibrosis

Dysplasia vs DesmoplasiaDysplasia Desmoplasia

- Premaligmant change, - Fibrosis in reactiona precursor to cancer to invasive cancer- Cervical dysplasia - Invasive breast (nipple retraction);

colon (apple core/napkin ring)

The classic shape of an infarct in the lung is: A. CircularB. LongitudinalC. RectangularD. Inverted ellipseE. Inverted triangle

D, wedge or triangle. Some infarcts are hemorrhagic (red) due to dual blood supply lung, liver. Kill one blood supply, other supply continues to pump hemorrhage.Most are pale.

MI Dating:- 0 hours- normal myocardium (?thrombus in coronary)- 1-2 hours- contraction bands; myoglobin + (very sensitive but nonspecific)- 4 hours- loss of nuclei/cell death; Tn and CKMB + (both sens. and spec.)- 12-24 hours- migration of neutrophils; most muscle dead- 72 hours +/- 24 hours- macrophages migrate;- 5-10 days (ave. 7)- muscle is totally removed; macrophages fibroblasts and

capillaries; no scar; Tn may remain elevated for 5-12 days- Several weeks- scar

Test q: A patient suffers an MI and dies 30hr later in the coronary care unit. At autopsy, the infarcted areaof the myocardium would most likely show: Coagulation necrosis w/neutrophil infiltration.

Test q: A 76y/o woman suffers a massive MI and dies in cardiogenic shock 20hr after its onset. Microscopicexam of her infarcted myocardium would be expected to demonstrate which of the following? Coagulativenecrosis w/few neutrophils.

Test q:A 49y/o male suffers an acute MI. He is treated w/angioplasty. Serum troponin I becomes elevated,but his recovery is otherwise uneventful. He is discharged 5 days after onset of chest pain. At day 9 post-MI, what would be the appearance of the infarcted area of the myocardium? Neutrophils, macrophages,

and fibroblasts.Test q: A patient is found dead at home. The patient has a history of angina. At autopsy the CK-MB wasnormal and the cardiac Troponin I was elevated. The heart shows an area of coagulative necrosis with

mixed inflammatory cells and evidence of new capillary growth and increased fibroblastic activity. The ageof the infarct is approximately: 5 days 1 week old. (Question was repeated with this answer: 3 days 1week old)

Test q: (slightly diff from one above)A patient is found dead at home. Patient has a history of angina. Atautopsy, the CK-MB was normal and the cardiac troponin I was elevated. The heart shows an area ofcoagulative necrosis with monocytes and evidence of new capillary growth and increased fibroblastic

activity The age of the infarct is approximately: 6-10 days old

Sclerotic lesion = SCARRING lesion.Scarring associated w/an invasive

tumor = desmoplasia

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Pathology Week 6 p18-35