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NORTH CAROLINA SOCIETY OF PATHOLOGISTS

2016Annual Meeting Shelley Lecture&

Focus on Breast Pathology

A collaboration between the North Carolina and South Carolina Societies of Pathologists

and the Shelley Foundation

SATURDAY, APRIL 16

This continuing medical education activity is jointly provided by the North Carolina Society of Pathologists and Southern Regional Area Health Education Center.

April 15-16, 2016 The Ballantyne Hotel, Charlotte, NC

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Lobular Carcinoma in Situand Problematic in Situ Lesions

of the Breast

Stuart J. Schnitt, M.D.Beth Israel Deaconess Medical Center and

Harvard Medical School,Boston, MA

Disclosures

• None

• Described essentially all key features of LCIS:

–Not clinically evident

–Histologic appearance (including loss of cohesion)

–Multicentricity

Am J Pathol 1941;17:491

Heterogeneity of LCIS

• Like DCIS, the term “LCIS” encompasses a heterogeneous group of lesions that differ in morphology, immunophenotype, genetic alterations and, possibly, clinical behavior

• Heterogeneity of LCIS has until recently been largely under-appreciated

LCIS: The Textbook View(Classical LCIS)

• Detected in <5% of breast biopsies (usually incidental finding)

• More common in pre-menopausal women

• Multicentric (~50%), bilateral (~30%)

• No distinctive mammographic features

• Considered to be a marker of increased breast cancer risk (~1%/yr; RR ~10x)

• Also now recognized as a precursor

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Classical LCIS

Type A Type B

Classical LCIS, Type B Cells

Loss of E-cadherin Expression: Defining Feature of LCIS (and ILC)

E-cadherin

• Calcium-dependent transmembrane protein

–Intercellular adhesion

–Maintenance of cell polarity

• Gene (CDH1) located on 16q22.1

• Integral component of adherens-type intercellular junctions

–Homodimerization of E-cad molecules on adjacent cells

–Intracellular domain linked to actin cytoskeleton via α-, β-, γ-, and p120 cateninsforming cadherin-catenin complex

E-cadherin

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Cadherin-Catenin Complex

Dabbs, AJSP, 2007Dabbs, AJSP, 2007

Loss of E-cadherin Expression in LCIS (and ILC)

• LOH at 16q22

• Often accompanied by inactivating mutations or promoter methylation of CDH1

• Deletions, transcriptional repression (via mechanisms other than hypermethylation), miRNA modulation

• Bi-allelic silencing of gene and loss of protein expression

LCIS: Loss of E-cadherin Expression

Non-Classical Forms of LCIS

• Some LCIS exhibit subtle deviations from classical type with regard to growth pattern/cytology

• Others show substantial deviation from classical type–Considerable nuclear pleomorphism

–Comedo necrosis

–Mammographic microcalcifications

• No standard terminology

Non-Classical Forms of LCIS of Clinical Importance

• Pleomorphic LCIS

• LCIS with necrosis

Problem for Pathologist

Distinction from DCIS

Problem for Clinician

Manage like classical

LCIS or like DCIS?

Pleomorphic LCIS• First described in 1996

• Post-menopausal women

• Growth pattern similar to classical LCIS

• Classical LCIS often co-exists

• Nuclear pleomorphism (2-3 fold variation in size)

• Mitoses may be present and numerous

• Comedo necrosis may be present – May present with mammographic

microcalcifications mimicking high grade DCIS

• Non-apocrine and apocrine types

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Non-Apocrine Type Non-Apocrine Type

E-cadherin

Non-Apocrine Type Apocrine Type

Apocrine Type

E-cadherin

Apocrine Type

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Biomarkers in Pleomorphic LCISChen, AJSP 2009

• When compared with classical LCIS, pleomorphic LCIS:

–Less often ER+

–Higher proliferation rate (Ki67)

–More often HER2+

Genomic Alterations in Pleomorphic LCIS by aCGH

Chen, AJSP 2009

• Consistently show 16q loss and 1q gain (“lobular signature”)

• When compared with classical LCIS:

–More frequent chromosomal losses and gains (particularly apocrine type)

Differences Between Classical and Pleomorphic LCIS

Classical LCIS Pleomorphic LCIS

Age Younger (premenopausal)

Older (postmenopausal)

Presentation Incidental Mammographic

ER + + or – (apocrine type)

HER2 - - or + (apocrine type)

Ki67 Low High

Genomic changes (aCGH)

Fewer More numerous (apocrine type)

Non-Classical Forms of LCIS of Clinical Importance

• Pleomorphic LCIS

• LCIS with necrosis

LCIS with Necrosis

• Post-menopausal women

• Cytologic features of classical LCIS (type A, type B, mixed)

• Filling and often massive distension of involved spaces with foci of comedo necrosis– May present with mammographic

microcalcifications mimicking high grade DCIS

• Included within “florid LCIS” category

LCIS with Necrosis

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LCIS with Necrosis

E-cadherin

Array-Based CGH of Florid LCISShin, Hum Pathol, 2013

• Like classical LCIS:

–16q losses and 1q gains

• But:

–Greater fraction genome loss

–More chromosomal breakpoints

–More frequent amplifications

How Does the Pathologist Distinguish These LCIS Variants from DCIS in Problematic Cases?

• Histologic features

• Adjunctive immunostains

Histologic Distinction Between LCIS Variants and DCIS

Feature LCIS Variants DCIS

Loss of cohesion Yes No

Intracytoplasmic vacuoles

More common Less common

Pagetoid ductal involvement


Associated classical

LCIS


Microacini Absent Present

Polarization of cells at periphery

Absent Present

Adjunctive Immunostains

• E-cadherin

• p120 catenin

• β-catenin

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Adjunctive Immunostains

• E-cadherin

• p120 catenin

• β-catenin

DCISE-cadherin Positive

Low grade High grade

LCISE-cadherin Negative

Limitations in Use of E-cadherin Immunostaining

• Loss of E-cadherin expression by IHC characteristic of LCIS, but……

• Presence of E-cadherin expression does not preclude diagnosis of LCIS in the context of appropriate histologic features

(i.e., E-cad positive = DCIS)

E-cadherin Expression in Lobular Lesions

• Aberrant E-cadherin expression in neoplastic cells themselves

• E-cadherin staining of benign cells associated with LCIS cells

• Technical issues


• Aberrant E-cadherin expression in neoplastic cells themselves

• E-cadherin staining of benign cells associated with LCIS cells


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Am J Surg Pathol 2008

Am J Surg Pathol 2010

•~15% of ILC show aberrant E-cad expression

ILC with Aberrant E-cadherin Expression

ILC with Aberrant E-cadherin Expression ILC with Aberrant E-cadherin Expression

E-cadherin Aberrant E-cadherin Expression in LCIS

• Few studies with small numbers

• 0-9% of cases

• Higher in our practice

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Patterns of Aberrant E-cadherin Expression in LCIS Cells

• Membranous

–Fragmented/partial/beaded (but may even be complete)

–Weak, moderate, strong

–Focal, diffuse

• Cytoplasmic

–Diffuse

–Perinuclear dot-like (Golgi) pattern

LCIS with Aberrrant E-Cadherin Expression




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PLCIS with Aberrrant E-Cadherin Expression

PLCIS with Aberrrant E-Cadherin Expression





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DCIS

vs

LCIS with aberrant E-cad Expression

Cadherin-Catenin Complex

Dabbs, AJSP, 2007Dabbs, AJSP, 2007

p120 catenin

β-catenin

Expected Expression of E-cadherin, p120 catenin and β-catenin

Normal

epithelium

LCIS and ILC DCIS and IDC

E-cadherin Membrane

staining

Absence of

membrane

staining

Membrane

staining

p120

catenin

Membrane

staining

Cytoplasmic

staining

Membrane

staining

β-catenin Membrane

staining

Absence of

membrane

staining

Membrane

staining

Expected Expression of E-cadherin, p120 catenin and β-catenin

Normal

epithelium

LCIS and ILC DCIS and IDC

E-cadherin Membrane

staining

Absence of

membrane

staining

Membrane

staining

p120

catenin

Membrane

staining

Cytoplasmic

staining

Membrane

staining

β-catenin Membrane

staining

Absence of

membrane

staining

Membrane

staining

E-cad

p120

β-catenin

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E-cad p120

E-cad

β-cat

But sometimes you just can’t be sure……

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E-cad

In situ carcinoma with ductal

and lobular features


• Aberrant E-cadherin expression in LCIS cells

• E-cadherin staining of benign cells


E-cadherin Staining of Benign Cells Can Be Mistaken for

Tumor Cell Staining in LCIS

• Normal or proliferating benign epithelial cells

• Myoepithelial cells

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• Aberrant E-cadherin expression in LCIS cells

• E-cadherin staining of benign cells


• Careful attention to pre-analytic and analytic factors needed to avoid false negative and false positive E-cadherin staining results

• Lack of appropriate antibody optimization and validation may result in spurious E-cadherin staining

Technical Issues

Technical Issues

Wells, AJSP 2013

E-cad, outside E-cad, repeated

Histopathology, 2016

Management of Non-Classical Variants of LCIS

Pleomorphic LCIS

• No clinical follow-up studies akin to those available for classical LCIS and DCIS

• Natural history/biologic behavior unknown

• ? More often associated with contemporaneous invasive cancer than classical LCIS

• Risk factors for local recurrence/progression to invasive ca not established

• Appropriate management uncertain

DATA

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PLCIS

E-cadherin neg

LCIS variant

Treat like LCISMore like DCIS than LCIS

Nuclear pleomorphism

Comedo necrosis

“Bad” biomarker profile

Treat like DCIS

PLCIS

E-cadherin neg

LCIS variant

Treat like LCISMore like DCIS than LCIS

Nuclear pleomorphism

Comedo necrosis

“Bad” biomarker profile

Treat like DCIS

What Does “Treat Like DCIS” Really Mean?

• Excision to negative margins?

Survey of 351 Surgeons: Frequency of Re-Excision for PLCIS at Margin

Blair, 2012

Re-Excision for

PLCIS at Margin

Frequency

Always 24%

Never 53%

Sometimes 23%



• Radiation therapy?



• Radiation therapy?

• In the absence of data, is it better to over-treat or under-treat?

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Management of Patients with Pleomorphic LCIS

WHO 2012

• “Caution should be exercised in recommending more aggressive management strategies such as excision to negative margins or mastectomy as a routine practice after a diagnostic surgical biopsy reveals pleomorphic LCIS.”

LCIS with Necrosis

• Same issues as those discussed for PLCIS

–Cells have a lobular phenotype but comedo necrosis is a worrisome feature

–Natural history unknown

–Treat like classical LCIS or like DCIS?

Non-Classical Variants of LCISPractice at BIDMC

• In core needle biopsy specimens:–Surgical excision

• In surgical excision specimens:–Management similar to DCIS

»Report margin status (but only for variant component when lesion is mixed with classical LCIS)

»Attempt to excise to negative margins

»?Radiation therapy

4/7/2016

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Chad A. Livasy, MDCarolinas Pathology Group

Adjunct Professor, UNC-Chapel Hill

Update on HER2 testing and

Molecular Tests in Breast Cancer

Disclosures

None.

Breast HER2 positive disease

Common features of HER2 positive disease

High-grade histology

Aggressive biology

Younger patients

Down-regulation of ER and PR expression

Press, et al. JCO:15, 2894-2904, 1997

HER2 Testing With IHC and FISH:

Complementary Approaches

HER2 gene amplification or protein overexpression can be assessed via FISH or IHC,

respectively

FISH and IHC are complementary methodologies, examining different aspects of the

biology of HER2-driven cancer1

HER2 gene amplification and protein overexpression have been shown to be

correlated2

IHC and FISH are equally efficient in identifying patients who are likely

to respond to HER2-targeted therapy

* IHC 3+ or FISH+.

1. Hicks DG et al. Am J Clin Pathol. 2008;129:263-273.

2. Hicks DG et al. Hum Pathol. 2005;36:250-261.

3. Wolff AC et al. J Clin Oncol. 2007;25:118-145.

4. Herceptin [prescribing information]. South San Francisco, CA: Genentech, Inc; October 20, 2010.

IHC FISH

4/7/2016

2

Pre-analytical factors

Cold ischemic time <1 hour

Fixation in 10% NBF for 6-72 hours

Decalcification (prefer agents that do not contain

hydrochloric acid)

Disclaimer statement added to negative reports

HER2 Positive Rate and Copy # Expect HER2 positive rate of 15-20%

Each lab should monitor their HER2+ rate and compare with expected positive rate

For HER2 ISH positive cases, there is no clear relationship between HER2 copy number and survival for patients treated with adjuvant trastuzumab

Positive cases near the cutpoint do benefit from HER2-targeted therapy

Reporting of results Report both ratio and HER2 copy #

If HER2 is positive based on HER2 copy #, helpful to add explanation in interpretation HER2 POSITIVE for amplification (based on HER2 copy number ≥6)

Case #1 45 yo woman with outside dx of breast cancer, node negative

Outside pathology results: IDC, Nottingham grade 3

Size=1.4 cm

Minor component of admixed DCIS

LVSI negative

Margins negative, all >2 mm

0/2 SLNs

pT1c pN0(sn)

Receptors (performed on prior core biopsy)

ER positive (3+, >90%), PR positive (3+, 80%)

HER2 2+ by IHC

HER2 negative by FISH (ratio=1.4; HER2 copy=2.0)

Case #1

Oncologist requested that tumor from excision specimen be

sent for Oncotype DX assay to guide chemoTx decision

Recurrence Score=High risk (58)

Single gene section= HER2 reported as Positive

Oncologist requested 2nd opinion on pathology

Case #1

4/7/2016

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Case #1 HER2 summary: HER2 positive with HER2 genetic

heterogeneity (approximately 40% of tumor cells are HER2 amplified by FISH and show HER2 overexpression 3+ by IHC)

Tumor sampled in the prior core biopsy was accurately classified as HER2 negative

HER2 FISH results:

Amplified region (ratio=8.4)

Non-amplified region (ratio=1.3)

Patient received 6 cycles adjuvant TCH chemotherapy

No evidence of recurrence to date

4/7/2016

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Intratumoral HER2 genetic heterogeneity

Not well studied, little data reported.

Two patterns of heterogeneity Geographic: Rare.

Likely clinically significant

Interspersed (scattered single cells with ratio >2.0): Not rare on ISH assays. Likely clinically insignificant

Histologic clues to possible HER2 heterogeneity Variable histology identified on excision specimen with

component of high-grade histology Zonal downregulation of ER and/or PR expression within a

tumor

4/7/2016

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HER2 Retesting (recent studies)

USCAP 2016 Carter et al. Repeat HER2 Testing on Grade 3 Invasive Breast Carcinoma

Resections (abstract 131)

169 grade 3 IBCs (HER2- on core), retested on excision

3 cases (1.8%) showed change to positive

Ballard et al. HER2 FISH Equivocal Category: Does Retesting Resolve

This Clinical Grey Zone? (abstract 114)

79 cases initially classified as equivocal

Approximately 1 in 4 converted to positive with retesting on excision

Most cases remained in the equivocal category

Case #2 48 yo woman presented with self detected breast mass, clinical T1 N0

mass Underwent US guided core biopsy

IDC, Nottingham grade 3

ER+ (3+, 95%), PR- (0%)

HER2 equivocal by IHC (score=2+)

HER2 equivocal by FISH (Ratio=1.7, HER2 copy=5.3)

Underwent needle-localized lumpectomy with SLN biopsy IDC, Nottingham grade 3

Size: 1.8 cm

Minor component of admixed high-grade DCIS

LVSI present

Margins negative (all >2 mm)

Micrometastasis (2.5 mm) involving 1 of 3 SLNs

pT1c N1mi(sn)

HER2 retesting on excision: Double equivocal by IHC and FISH

Ratio=1.6, HER2 copy=5.1

Case #2

Details of case were discussed with treating oncologist

HER2-targeted therapy was added to this patient’s

chemotherapy regimen based on high-risk features

HER2 equivocal

Oncologist treatment practices for HER2 equivocal cases is

variable

Important to regularly discuss these cases with treating

oncologists

Options for HER2 equivocal Test alternate specimen, block or site (e.g. positive lymph node)

Repeat HER2 testing in same specimen using an alternate probe for centromeric region or for another gene in chromosome 17 not expected to co-amplify with HER2 (e.g. SMS, RARA, p53) SMS and RARA are frequently amplified (data from TCGA) TP53 amplifications less common Different ratios often obtained with use of alternative chromosome 17

reference genes, but clinical significance is unknown

Case discussion with treating oncologist to review clinicopathologic findings and individualized decision on HER2-targeted therapy Oncologist may chose to give HER2 targeted therapy for equivocal results,

particularly for high-risk tumors in which chemotherapy is planned

If there is uncertainty regarding chemotherapy, could send Oncotype Dx for information on chemotherapy benefit Single gene RT-PCR HER2 assay is typically resulted as negative

4/7/2016

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HER2 equivocal From our 2015 files

1325 tumors tested for HER2 6% were classified as equivocal

Actual % likely less due to retesting of equivocal cases

HER2 FISH equivocal definition revised in 2013

Ratio <2.0, with HER2 copy number ≥4 and <6

Very little clinical data on response to HER2 targeted therapy for these patients

Based in part on understanding that there is instability in the genomic content of chromosome 17 centromeric region and these variations affect the HER2/CEP17 ratio

Equivocal HER2 FISH Results on Breast Core Biopsy with Ratio <2.0:

Repeat HER2 Testing on Excision Specimens Impacts Patient ManagementC. Livasy, B. Calhoun, S. Limentani

Levine Cancer Institute and Carolinas Pathology Group, Charlotte, NC

ResultsAbstract

Objective

Results

Conclusions

Evaluate the clinical impact of repeat HER2 testing by FISH on

excision specimens from patients with an invasive mammary carcinoma showing an equivocal HER2 result on the diagnostic core

biopsy who would otherwise not be eligible for HER2-targeted

therapy based on a HER2:CEP17 ratio <2.0.

Background: In the first generation HER2-targeted adjuvant clinical trials, a ratio of 2.0 was used as the

cutpoint to determine eligibility for trastuzumab therapy for patients whose tumors were tested by FISH.

The ASCO/CAP guidelines subsequently defined cases showing a ratio of 1.8-2.2 as equivocally

amplified. HER2 equivocal tumors present a challenge to oncologists who must decide whether or not to give HER2-targeted therapy. There are no clear evidence-based guidelines for how to resolve the HER2

status for equivocally amplified tumors. The identification of HER2 genetic heterogeneity within tumors

raises the possibil ity that sample size may be an important factor in accurately determining HER2 status,

particularly for cases near the cutpoint. This study evaluates the potential clinical impact of HER2 retesting on excision specimens for patients with HER2 FISH equivocal results showing a ratio <2.0 on

core biopsy, who would otherwise not be eligible for HER2 targeted therapy.

Design: A total of 35 breast core biopsy specimens were identified from our database showing invasive mammary carcinoma and an equivocally amplified HER2 status (ratio <2.0) who had retesting of HER2

status by FISH on the subsequent excision specimen. The HER2 ratios from the core biopsy and excision

specimen were compared. Changes in HER2 status between the core biopsy and excision specimen were

noted using ASCO/CAP criteria.

Results: A definitive change in the classification of the HER2 status was observed in 24 (68%) cases.

Twenty cases (57%) reclassified as negative, 4 cases (11%) reclassified as positive, and 11 cases (31%)

remained equivocal. Three of the patients with HER2 equivocal results on the excision specimen demonstrated a ratio >2.0. Using a ratio of 2.0 as the cutpoint for determining eligibility for HER2 targeted

therapy, a total of 7 (20%) of patients became eligible for trastuzumab therapy. The four patients who

showed a definitive reclassification to HER2-positive status showed ratios of 4.0, 3.0, 2.5 and 2.4.

Conclusion: For patients with equivocally HER2 amplified results on core biopsy showing a ratio <2.0,

repeat HER2 FISH testing on a larger volume of invasive carcinoma from excision specimens results in

definitive reclassification of HER2 status for a significant number of patients. Approximately 1/5 of patients

became eligible for HER2-targeted therapy based on results from the excision specimen. These results support the ASCO/CAP recommendations for further testing of cases with HER2 equivocal results.

• 24 (68%) tumors were reclassified as amplified or non-

amplified based on repeat FISH testing on resection material.

• 7 (20%) patients became eligible for HER2-targeted therapy based on results from the resection specimen.

• 4 (11%) tumors showed a definitive reclassification to HER2 amplified (ratios 4.0, 3.0, 2.5 and 2.4). All of these

cases showed an average of 4 or more HER2 signals per

nucleus.

• 11 (33%) tumors remained in the equivocal category. 3 of

these tumors demonstrated a ratio ≥2.0 and an average of 4 or more HER2 signals per nucleus. One of these

tumors demonstrated a ratio of 2.0, >6 HER2 signals/nucleus and 3+ staining by IHC.

• HER2 IHC conclusively resolved 4 cases showing a ratio of 1.8 or 1.9 as negative where the HER2:CEP17 ratio

was elevated due to decreased CEP17 copy numbers.

• 20 of 25 (57%) patients were reclassified as negative

based on the excision specimen.

• All equivocal tumors were Nottingham grade 2 or 3

• For patients with equivocally HER2 amplified results on

core biopsy who do not meet criteria for HER2-targeted therapy, repeat HER2 testing on a larger volume of

tumor from resection specimens impacts patient

management and should be performed.

• These findings support the American Society of Clinical

Oncology/College of American Pathologists recommendations for further testing of cases with an

equivocal HER2 result.

• In this study, 1 in 5 patients became eligible for HER2-

targeted therapy based on retesting of resection specimens. Given this relatively high rate of conversion

to positive in a cohort of patients with an initial ratio of 1.8

or 1.9 on core biopsy, algorithms for repeat HER2 testing on resection specimens from patients showing a

negative result on core biopsy should be explored.

Printed by

Methods

Our institution employs fluorescent in situ hybridization (FISH) as the

primary methodology for determining HER2 status of invasive mammary carcinomas. We evaluate >1000 cases each year by

FISH with an annual HER2 equivocal rate of approximately 6%.

From these cases, a cohort of patients was identified in which the initial HER2:CEP17 ratio on the diagnostic core biopsy was reported

as equivocal with a ratio <2.0 (ratio of 1.8 or 1.9) and repeat HER2 FISH results on the subsequent excision specimen were available

for comparison. All cases were tested with the Vysis PathVysion

HER2 DNA Probe Kit (Abbott Molecular). Cases showing an equivocal ratio were evaluated by two different observers, each

scoring a total of 40 cells. The HER2 status of tumors was determined using ASCO/CAP criteria (<1.8 negative, 1.8-2.2

equivocal and >2.2 positive). In this cohort of patients, the HER2

ratios from the core biopsy and excision specimen were compared. Changes in HER2 status between the core biopsy and excision

specimen were noted. Tumor grade and size from each of these cases was recorded.

• A total of 35 patients were obtained from recent files meeting criteria for

inclusion. The detailed FISH results from the core biopsy and excision specimen are summarized in the table below.

Case Ratio

core

HER2 CEP17 Result

core

Ratio

excision

HER2 CEP17 Result

excision

Size/Grade

1 1.9 5.65 3.02 Equiv 4.0 7.07 1.77 Amp 1.8/G3

2 1.9 2.85 1.5 Equiv 3.0 5.43 1.8 Amp 1.5/G2

3 1.9 3.57 1.85 Equiv 2.5 4.8 1.95 Amp 3.4/G3

4 1.9 4.97 2.57 Equiv 2.4 5.05 2.07 Amp 2.0/G2

5 1.9 4.58 2.45 Equiv 2.0 7.35 3.63 Amp* 3.0/G3

6 1.9 3.65 1.88 Equiv 2.1 4.8 2.25 Equiv 1.5/G2

7 1.9 4.77 2.50 Equiv 2.1 4.9 2.32 Equiv 1.1/G2

8 1.9 2.7 1.41 Equiv 1.9 2.12 1.12 Equiv** 1.4/G2

9 1.9 2.98 1.6 Equiv 1.8 2.5 1.57 Equiv** 1.8/G2

10 1.9 3.78 1.9 Equiv 1.8 2.43 1.38 Equiv** 2.5/G3

11 1.8 4.07 2.2 Equiv 1.8 4.32 2.42 Equiv 2.2/G3

12 1.8 2.87 1.6 Equiv 1.8 3.75 2.07 Equiv 1.0/G3

13 1.8 4.82 2.62 Equiv 1.8 3.8 2.1 Equiv 1.2/G3

14 1.9 4.15 2.2 Equiv 1.8 4.24 2.34 Equiv 0.8/G2

15 1.8 3.75 2.07 Equiv 1.8 2.87 1.6 Equiv** 1.0/G3

16 1.9 3.67 1.9 Equiv 1.7 2.85 1.68 Neg 1.7/G2

17 1.8 3.25 1.8 Equiv 1.1 1.68 1.48 Neg 2.0/G3

18 1.8 4.82 2.62 Equiv 1.5 5.1 3.5 Neg 1.2/G3

19 1.9 4.77 2.55 Equiv 1.7 4.21 2.5 Neg 5.2/G3

20 1.8 4.2 2.27 Equiv 1.7 4.32 2.47 Neg 2.5/G3

21 1.9 3.91 2.1 Equiv 1.7 3.97 2.4 Neg 2.0/G2

22 1.9 3.33 1.73 Equiv 1.6 3.1 1.9 Neg 0.5/G2

23 1.9 4.95 2.62 Equiv 1.6 4.1 2.6 Neg 2.1/G2

24 1.9 4.7 2.45 Equiv 1.6 4.95 3.18 Neg 2.0/G2

25 1.8 4.22 2.35 Equiv 1.4 4.7 3.3 Neg 1.5/G3

26 1.8 3.0 1.67 Equiv 1.4 2.9 2.05 Neg 1.9/G3

27 1.8 3.53 2.00 Equiv 1.4 1.95 1.45 Neg 1.3/G2

28 1.9 4.1 2.12 Equiv 1.4 2.48 1.78 Neg 3.0/G2

29 1.9 5.3 2.8 Equiv 1.3 4.65 3.6 Neg 0.6/G2

30 1.9 3.4 1.75 Equiv 1.2 2.3 1.95 Neg 2.5/G2

31 1.8 3.4 1.93 Equiv 1.2 2.05 1.78 Neg 2.7/G3

32 1.9 3.85 2.0 Equiv 1.2 2.23 1.78 Neg 2.5/G3

33 1.9 4.66 2.39 Equiv 1.3 3.97 3.1 Neg 1.6/G3

34 1.9 3.45 1.78 Equiv 1.1 4.7 4.1 Neg 5.5/G3

35 1.8 3.55 1.92 Equiv 1.2 2.48 2.15 Neg 1.8/G3

*Equiv by ratio, amp by HER2 copy number (>6 HER2/nucleus), IHC=3+ **IHC 0 or 1+

HER2 evaluation with RT-PCR No current defined utility in resolving equivocal/borderline cases

Most double equivocal cases by IHC/FISH are negative by Oncotype RT-PCR single gene assay (personal experience)

High False-Negative Rate of HER2 Quantitative Reverse Transcription Polymerase Chain Reaction of the Oncotype DX Test: An Independent Quality Assurance Study (Dabbs et al. J Clin Oncol 29:4279-85, 2011) N=843

Of 36 FISH positive cases: 10 positive, 12 equivocal and 14 (39%) negative by RT-PCR

“Unacceptable” false negative rate for Oncotype DX

Probably bias towards cases that are difficult to classify HER2 status

HER2+ tumors are rarely sent for Oncotype

HER2 low study NSABP B-47

To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP)

improves invasive disease-free survival (IDFS) in women with resected node-positive or high-

risk node-negative breast cancer which is reported as HER2-low by all HER2 testing

performed.

Polysomy/monosomy 17 CEP17 probe added to normalize for “polysomy 17” (thought to be due to

increased copies of chromosome 17)

CGH have subsequently demonstrated that whole chromosome polysomy is exceedingly rare Yeh, et al. Clinical validation of an array CGH test for HER2 status in breast cancer

reveals that polysomy 17 is a rare event. Mod Pathol 22: 1169-75, 2009.

Much more complex than initially thought Gains and losses seen throughout entire chromosome

Variations in CEP17 significantly affect HER2/CEP17 ratio.

Monosomy 17 with ratio >2.0

These cases are rare (~1% of FISH cases in our experience)

HER2 copy# <4

These patients were included in first generation trastuzumab

clinical trials

Little clinical data on benefit of HER2-targeted therapy

Often discordant with IHC

4/7/2016

7

Other problematic ISH scenarios

Loss of entire chromosome 17

Single signals for both HER2 and CEP17

Reported as non-amplified

Total loss of CEP17 signals in tumor cells

Cannot calculate an accurate ratio; report HER2 copy #

Often resolved with IHC

Could try alternate reference probe

Co-amplification of HER2 and CEP17

Problem resolved for most cases using current guidelines

Most cases are 3+ by IHC

HER2 Status May Change Between Primary Breast Cancer

Diagnosis and Metastatic Disease

* Percentages are a measurement of change from negative to positive HER2 status.† Studies have also shown that patients’ HER2 status may change from positive in the primary diagnosis to negative in metastatic disease.3,4

1. Simmons C et al. Ann Oncol. 2009;20(9):1499-1504; 2. Guarneri V et al. Oncologist. 2008;13(8):838-844; 3. Fabi A et al. Clin Cancer Res. 2011;17(7):2055-2064; 4. NCCN Clinical Practice Guidelines in OncologyTM: Breast Cancer V2.2011. National Comprehensive Cancer Network Web site. Accessed November 23, 2011; 5. Pegram M, Slamon D. Semin Oncol. 2000;27(5)(suppl 9):13-19.

Studies show HER2 status changes* in 9% to 16% of breast cancer cases

from early stage to late stage

HER2 Status Negative to Positive

Simmons et al 9% (2/22)

Guarneri et al 16% (10/61)

Fabi et al 11% (12/112)

Due to the aggressive nature of HER2-positive disease, it is advisable to rebiopsy and

retest upon first recurrence of metastatic disease when original results were HER2-negative

or unknown.

HER2 Testing in DCIS

No current indication

Awaiting results from NSABP B-43

HER2+ (confirmed centrally) treated with lumpectomy, final

margins negative

Randomized to low-dose trastuzumab/WBI vs WBI alone

Primary end point

Ipsilateral IBC/DCIS recurrence

HER2+ rate observed for DCIS=35%

What Makes a Clinically Useful Assay?

•Cost-neutral/saving, cost effective, better resource use

Economic Utility

•Affects treatment decision making

Clinical Utility

•Outcome endpoints(i.e. prognostic, predictive)

Clinical Validity

•Reproducible and reliable

Analytic Validity

•Consensus on analytic and clinical validity and clinical and economic utilityGuidelines

Adapted from Simon et al. J Clin Onc. 2005. Hayes et al. Breast. 2003.

4/7/2016

8

Molecular tests for early stage, ER+,

invasive breast carcinoma Oncotype DX (RT-PCR gene expression, 21 genes)

Central testing

FFPE tissue

Three tier risk classification (low, intermediate and high risk)-10 years

MammaPrint (RNA gene microarray, 70 genes) Central testing (MammaPrint, BluePrint, TargetPrint)

Fresh or FFPE tissue

Binary risk classification (low and high risk)-10 years

May send ER- tumors

Prosigna (Hybridization with gene specific labels-nCounter, 58 genes) Local testing

FFPE tissue

Three tier risk classification (node negative), two tier (1-3 node positive)-10 years

Requires pathologist involvement for adequacy assessment and isolation of tumor for analysis

Practicing Precision MedicineThe Oncotype DX® Breast Cancer Assay

16 Breast Cancer-Related Genes

ER

PR

Bcl2

SCUBE2

GRB7

HER2

Ki-67

STK15

Survivin

Cyclin B1

MYBL2

Stromelysin 3

Cathepsin L2GSTM1

CD68

BAG1

Beta-actin GAPDH RPLPO GUS TFRC

Estrogen Proliferation HER2 Invasion Others

5 Reference Genes

Paik et al. N Engl J Med. 2004.

The Recurrence Score® Result Reveals Individual

Tumor Biology for ER+ Breast Cancer

Paik et al. N Engl J Med. 2004; Paik et al. J Clin Oncol. 2006.

Dis

tan

t R

ec

urr

en

ce

at

10

Ye

ars

Recurrence Score Value

40%

35%

30%

25%

20%

15%

10%

5%

0%

0 5 10 15 20 25 30 35 40 45 50

Low Recurrence Score Disease

Indolent

Hormonal therapy–sensitive

Minimal, if any, chemotherapy benefit

High Recurrence Score Disease

Aggressive

Less sensitive to hormonal therapy

Large chemotherapy benefit

Continuous Biology

TAILORx: A Clinical Trial Assigning

Individualized Options for Treatment (Rx)

Sparano et al. N Engl J Med. 2015.

Oncotype DX® Assay

Secondary Study Group RS <11

~29% of Population

Arm AHormonal Therapy

AloneN=1626 (16.1%)

Primary Study Group

RS 11-25 ~44% of Population

Randomize

N=6885 (68.4%)

Secondary Study Croup

RS >25 ~27% of Population

Arm DChemotherapy Plus Hormonal TherapyN=1520 (15.5%)

Eligible 10,253 pts

prospectively enrolled

(2006-2010)

RS: Recurrence Score® result

Published in

NEJM 2015

Patients in Arm A

were predominantly

treated with AI (59%)

and tamoxifen (34%)

Arm BHormonal Therapy

Alone

Arm C Chemotherapy Plus Hormonal Therapy

Study Arms for Primary Analysis

To be reported at a later date

Patients with Recurrence Score® Results <11 Have Less than 1% Risk of Distant Recurrence at 5 Years

Sparano et al. N Engl J Med. 2015.

1.00

0.95

0.90

0.85

0.80

0 12 24 36 48 60

Months

5 year DRFI Rate

99.3%

(95% CI 98.7%, 99.6%)

Dis

tan

t re

cu

rren

ce-f

ree in

terv

al

pro

bab

ility

n=1,626

Median follow-up 69 months

0.00

Diagnosed between 2004-11

n= 379,103

With Recurrence

Score

n= 46,733

HR+, HER2- non-metastatic

n= 45,287

Node-negative

n= 40,134

Age 40-84

n= 38,568

SEER Breast Cancer Registry Study

Design• Characterize the Oncotype DX® assay testing and known chemotherapy (CT) use by nodal

status in hormone receptor-positive (HR+) invasive breast cancer

• Determine prospective breast cancer-specific mortality (BCSM) outcomes by Recurrence

Score® result and clinical and pathologic features

• In a pre-specified analysis of N0, HR+, HER2- patients aged 40-84 years

• In subgroups with N0 and node-positive (N+; micrometastatic and 1-3 positive nodes) disease,

including subgroups often under-represented in clinical trials

Shak et al. SABCS 2015.

4/7/2016

9

5-year BCSM in Recurrence Score® Groups by Known

Chemotherapy (CT) Use: ER+, N0, HER2(-) Patients

Shak et al. SABCS 2015.

Recurrence Score Group Low Intermediate High

Known Chemotherapy 7% 34% 69%

No or Unknown Chemotherapy 93% 66% 31%

Van De Vijivern MJ, et al. N Engl J Med.2002

70 prognosis genes

Tum

or

sam

ple

s

Metastases: w

hite

=+70-Gene cDNA Microarray Expression

Profile (MammaPrint)

Study included samples from heterogeneous

patients with breast cancer, 141/295 were node

negative and not treated with adjuvant therapy

2 outcomes – distant recurrence or not w/o

adjuvant therapy

FDA Clearance 510(k) for fresh or frozen tumor,

CLIA certified for formalin-fixed paraffin-

embedded (FFPE)

No distant metastasesGroup (< 5 yrs)

Full genome gene

expression analysis

Distant metastasesGroup (< 5 yrs) Prognosis reporter genes

Netherlands Cancer InstituteFrozen Tissue Bank

Tumor samples of known clinical outcome

50

RASTER study Drukker et al. A prospective evaluation of a breast cancer

prognosis signature in the observational RASTER study. Int J

Cancer. 2013. 133(4):929-936.

427 patients (cT1-T3 N0 M0, ages 18-61)

219 patients classified as “low risk” by 70-gene assay

85% of these patients did not receive chemotherapy

97% were disease free after 5 years

208 patients classified as “high risk” by 70-gene assay

81% of these patients received chemotherapy

91% were disease free after 5 years

Conclusion: Assay identifies a group of woman who may omit

adjuvant chemotherapy without compromising outcome.

PAM50 ROR Assay by

NanoString nCounter®

Extract RNAfrom FFPE

tumor sample

Run RNA & PAM50 CodeSet on nCounter Analysis System

Capture patient expression profile

Calculate Risk of Recurrence (ROR) Score

Determine Intrinsic Subtype Through Pearson’s Correlation to Centroids

Prosigna Pathologist Involvement

Pathologist circles region of viable tumor, excluding

surrounding non-tumor tissue

Tumor cellularity estimated within circled area

>10% cellularity, >4 mm squared required

Tumor tissue from unstained slides used for analysis

4/7/2016

10

Goals for Neoadjuvant Therapies for Locally

Advanced Breast Cancer

• Locally advanced breast cancers represent approximately 4% of all breast cancers diagnosed in the United States1

• Management of locally advanced breast cancers has evolved over the last two decades and neoadjuvant systemic therapy is frequently used prior to surgery and/or radiation2-4

• The goals of neoadjuvant therapy are to improve surgical outcomes and options:

– For operable breast cancer: Increase ability for breast conserving surgery in those who would otherwise require mastectomy

– For inoperable breast cancer: Down-staging of large tumors to improve surgical options and outcomes

• Gene signatures can assist in selection of systemic neoadjuvant treatment by identifying patients more/less likely to respond to therapy5-10

1. Anderson et al. J Clin Oncol. 2003. 6. Chang et al. Breast Cancer Res Treat. 2008. 2. Gralow et al. J Clin Oncol. 2008. 7. Yardley et al. SABCS 2011. Abstract P5-13-09.3. Kaufmann et al. J Clin Oncol. 2006. 8. Akashi-Tanaka et al. Breast. 2009.

4. Schwartz et al. Cancer. 2004. 9. Masuda et al. ASCO 2011. Abstract 558.5. Gianni et al. J Clin Oncol. 2005. 10. Zelnak et al. ASCO 2013. Abstract 562.

Guiding Neoadjuvant Therapy Selection

Sample Case

Patient: 72 years old woman, desires BCT

Medical history

ILC in the right breast

Findings

Vague, poorly demarcated abnormality MRI (5.6 cm)

Tumor is ER+/PR+/HER2- (needle core biopsy)

Characteristic Description

Tumor size 5.6 cm

Tumor grade 1

Lymph nodes No palpable adenopathy

ER/PR status ER+/PR+

HER2 status Negative

Oncotype DX®

Recurrence Score®10

• Recurrence Score result of 10 indicates that she is more likely to respond to neoadjuvant

endocrine therapy and less likely to respond to neoadjuvant chemotherapy than would a

patient with a high score

• Based on this, the doctor and patient decided to proceed with neoadjuvant endocrine

therapy

Guiding Duration of Adjuvant Endocrine

Therapy

Breast Cancer Index Genetic Assay

Marketed to help oncologist decision to extend or end

endocrine therapy at year 5 and beyond for patients with early

stage ER+, node-negative, IBC who are distant recurrence-free

Also reports individualized risk of late recurrence of breast

cancer (years 5-10)

Multi-gene quantitative RT-PCR assay

Genes:

Extended endocrine therapy: HoxB13/IL17BR

Risk of late recurrence: BUB1B, CENPA, NEK2, RACGAP1, RRM2

DCIS Molecular Testing: Better Tools Are Needed

• Better tools to provide an individualized risk estimate that is based on the underlying

tumor biology are needed1

• There is a need for tests that:

– Provide an individualized estimate of LR risk

– Provide confidence that you are making the right treatment recommendation

• When clinical and pathologic features are incongruent

• Confirming that a patient has a low risk of LR and could forego radiation

– Identify patients thought to be low risk based on clinical and pathologic features but

actually have higher-risk disease

1. Allegra et al. J Natl Cancer Inst. 2010.

How can genomics address this need?

4/7/2016

11

DCIS Score™ Result: Gene Selection

Solin et al. J Natl. Cancer Inst. 2013.

PRKi-67

STK15

Survivin

Cyclin B1

MYBL2

GSTM1

Beta-actin

GAPDH

RPLPO

GUS

TFRC

Hormone Receptor GroupProliferation Reference

The DCIS Score result:

• Is a continuous variable

• Is a quantitative risk assessment (number between 0-100)

• Reflects each individual patient’s tumor biology

PR: progesterone receptor

DCIS Score™ Result: 10-Year LR in E5194(low/intermediate grade , ≤2.5 cm or high grade, ≤1 cm ; ≥3 mm margin)

Solin et al. J Natl. Cancer Inst. 2013.

Any Local Recurrence

The ECOG E5194 study validated the DCIS Score result as a predictor of LR

(increasing DCIS Score corresponds to increasing risk)

• Any DCIS or invasive LR

• An invasive LR

Invasive Local Recurrence

CI: confidence interval; HR: hazard ratio

NGS testing in metastatic breast

cancer

Defining utility in breast cancer clinical decision making is a

work in progress

Objective is to identify actionable mutations to target

Very little data to date to support tumor mutation profiling

in breast cancer outside of research setting

May serve as a screening tool for clinical trial enrollment

1

Page 1

A Contemporary View of Lumpectomy Margin Evaluation

Stuart J. Schnitt, M.D.

Department of Pathology

Beth Israel Deaconess Medical Center and Harvard Medical School

Boston, MA

Disclosures

• None

Local Treatment of Breast Cancer

• Breast conserving therapy now standard treatment for patients with invasive breast cancer

–Breast conserving surgery and radiation therapy

–Breast conserving surgery alone (for selected patients)

• Associated with high levels of local tumor control

Local Treatment of Breast Cancer

• Small proportion of patients develop local recurrence in the treated breast

• Minimizing local recurrence is important

–Emotional distress

–Adverse effect on survival

Risk Factors for Recurrence in the Conservatively Treated Breast

• Clinical factors

–Young age

• Treatment factors

–Extent of excision

–Details of radiation therapy

–Use of systemic therapy

• Tumor factors

–Gross multicentricdisease

–Extensive intraductalcomponent

–Molecular subtype

–Margins

Basics of Margin Evaluation

• Margin evaluation is an exercise in probabilities (not absolutes)

• Patients with positive margins are more likely to have residual disease at or near the primary site than those with negative margins

• But

–A positive margin does guarantee residual disease

–A negative margin does not preclude extensive residual disease

2

Page 2

The Goal of Margin Evaluation

• IS NOT to ensure that there is no residual tumor in the breast

The Goal of Margin Evaluation

• To identify those patients more likely to have a large residual tumor burden and who, therefore, require further surgery (re-excision or mastectomy)

• To identify those patients unlikely to have a large residual tumor burden and who, therefore, are suitable candidates for breast conserving therapy without further surgery

Limitations of Margin Assessment

• Technical and methodogical

• Definition and interpretation

• Distribution of tumor in the breast

• Breast cancer biology

• Impact of systemic therapy

Technical and Methodologic Issues

• The “pancake phenomenon”

Am J Surg 2002 Am J Surg 2002

Occurs even in the absence of compression

for specimen radiography

3

Page 3



• Specimen orientation

--In addition to orienting specimen using S and L sutures, a 3rd stich was randomly added to another margin

Ann Surg Oncol 2009

S

L--Surgeon-pathologist

discordance

about 3rd margin location

in 31% of cases




• Problems with ink

Inking of Specimen Margins

Unoriented Specimen Oriented Specimen

Resident 1 Resident 2

Resident 3 Resident 4

X X

XX

4

Page 4

• Experimental model using oriented, partially filled water balloon

• Three volunteers painted six surfaces

• Area of each color on surface quantitated by image analysis

• Area of some painted surfaces differed by as much as 100% between painters

• Last surface painted on average 18% larger than the rest

Int J Br Cancer 2013

Where is the margin?

TUMOR

Is this the orange margin or the blue margin?

ColorOverall

Accuracy (%)

AJCP, 2014

5

Page 5

ColorOverall

Accuracy (%)

AJCP, 2014




• Problems with ink

• No uniform sampling method; sampling error

Sampling of Lumpectomy Specimens

• Ranges from limited sectioning to total sequential embedding

• Even with total, sequential embedding, only a small proportion of the specimen is examined microscopically

How “Total” is Total Sequential Embedding?

• 4.2 cm lumpectomy specimen

• Cut at 3mm intervals resulting in 14 slices

4.2 cm

• Each slice embedded in

paraffin and cut at five

microns

• Results in 14 five micron

sections

• 70 microns of tissue

examined from a 4.2cm

specimen =

0.2% of specimen

Complete HistologicExamination of this 4.2 cm

Lumpectomy Specimen Would Require

8400 slides

Definitions and Interpretive Issues

6

Page 6

At many institutions

• Proscribed minimum margin distance required for breast conserving treatment based on

–data from retrospective studies

–local lore/urban legend

–how/where surgeons were trained

• 25+ years after randomized trials, no general agreement among surgeons or radiation oncologists as to what constitutes an adequate negative margin–No margin width about which >50% of surgeons

or radiation oncologists agree is “adequate” or “negative”

–All available data from retrospective studies

– Issue never addressed in randomized trials

What is an Adequate Margin?

What is an Adequate Margin?Surgeons (Azu, 2010)

What is an Adequate Margin?Radiation Oncologists (Taghian, 2005)

McCahill, JAMA, 2012

Range 0-70%

Why does it matter?

• Extent of surgical resection most important determinant of cosmetic outcome

7

Page 7

Why does it matter?

• Re-excisions associated with

–Patient anxiety

–Poor cosmesis

–Morbidity

–Cost

–Patients opting for mastectomy

How Well Does Any Given Margin

Measurement Reflect Reality?

2mmTu

mo

r

2mm <1mmTu

mo

r

Tu

mo

r

Distribution of Tumor in the Breast

Tumor

<2 cm

2 cm

3 cm

4 cm

42% (18% inv, 24% CIS)

17% (8% inv, 9% CIS)

10% (5% inv, 5% CIS)

Cancer, 1985

8

Page 8

Negative Margin Width and Local Recurrence

If this is the case, do millimeters really matter?

• 14,571 patients from 21 studies

• No significant difference in LR rates associated with threshold margin widths of 1 mm, 2 mm or >5 mm when adjusted for use of radiation boost or endocrine therapy

Eur J Cancer 2010

Breast Cancer Biology

Impact of Breast Cancer Biology on Local Recurrence

• More biologically aggressive types (e.g., triple negative breast cancer) associated with higher local recurrence rates regardless of margin width

Arvold , JCO 2011

LUM A

HER2

TN



• OncotypeDX recurrence score (developed to predict likelihood of distant recurrence) also predicts loco-regional recurrence (Mamounas,

2010)

9

Page 9



• OncotypeDX recurrence score (developed to predict likelihood of distant recurrence) also predicts loco-regional recurrence (Mamounas,

2010)

• Wider margins don’t overcome bad biology

Impact of Systemic Therapy

Effective Systemic Therapy Reduces Local Recurrence

No Systemic Therapy

Systemic Therapy

NSABP B14

ER+, N-

(systemic Rx: none vs Tam)

14.7% 4.3%

NSABP B13

ER-, N-

(systemic Rx: none vs MF)

13.4% 2.6%

All patients in both studies had NSABP-defined negative margins

(i.e., no tumor touching ink)

TAM

OX

IFEN

C

HEM

OTH

ERA

PY

EBCTCG Overview. Lancet 2005;365:1687

Lack of agreement

regarding definition of a

negative margin

Common use of re-

excision (including in pts

already with no ink on

tumor)

Recognition of impact of

contemporary systemic

therapies on reducing LR

rates

Better understanding of

tumor biology

Joint SSO-ASTRO Consensus

on Margins in Invasive Breast Cancer

Co-chairs: Monica Morrow SSO

Meena Moran ASTRO

ASBS Suzanne Klimberg

ASCO Marina Chavez MacGregor

ASTRO Jay Harris, Gary Freedman, Janet Horton

CAP Stuart Schnitt

SSO Armando Giuliano, Seema Khan

Advocate Peggy Johnson

Methodologist Nehmat Houssami

Joint SSO-ASTRO Consensus

on Margins in Invasive Breast CancerJuly 12-13, 2013

Participants:

Funded by a grant from Susan G. Komen

10

Page 10

Feb. 10, 2014

Annals of Surgical Oncology Article

Most Cited in 2014-2015

SSO-ASTRO Consensus

• Applies only to patients with invasive breast cancer treated with breast conserving surgery and whole breast irradiation

• Does not apply to: Patients treated with partial breast

irradiation Patients treated with lumpectomy without

radiation Patients treated with neoadjuvant

chemotherapy Patients with DCIS

SSO-ASTRO ConsensusPrimary Evidence Base

Ann Surg Oncol, 2014

Study-level meta-analysis of 33 studies (870 abstracts screened): 28,162 patients

1,506 local recurrences

Study eligibility: > 90% Stage I+II

Minimum mean/median f/u 4 yrs

LR in relation to margin status

Whole breast RT

Margins Meta-analysis: Results

Margins and LR adjusted for length of follow-up

OR 95% CI p-value

Margin status

Negative 1.0 < .001

Positive/Close 1.96 1.72-2.24

Median Recruitment Year: 1990

Median Prevalence of LR: 5.3% (2.3-7.6%)

• Adjusting for age, yr of recruitment, endocrine rx did not change

results

• Increased local recurrence rate associated with positive margins

not nullified by radiation boost, systemic therapy, or favorable

biology


Margins and LR adjusted for length of follow-up

OR 95% CI p-value

Margin status

Negative 1.0

Close 1.74 1.42-2.15

Positive 2.44 1.97-3.03 < .001

Notes:

1. Heterogeneity in definitions of positive and close margins

2. Panel felt that analysis of specific margin widths supersedes this


Threshold Distance # studies # subjects/# LRs OR* 95% CI

1 mm 6 2376/235 1.0

2 mm 10 8350/414 0.91 0.46-1.80

5 mm 3 2355/103 0.77 0.32-1.88

Relationship Between LR and Threshold Margin Distance

* Adjusted for length of f/u

p (association) = 0.90

p (trend) = 0.58

11

Page 11

Impact of Margin Width on LRTreatment Covariates

Margin Width: OR*

Treatment

Covariate

# studies 1 mm 2 mm 5 mm p-value

Endocrine Rx 16 1.0 0.98 0.90 0.95

Radiation Boost 18 1.0 0.82 0.92 0.86

*Adjusted for length of f/u

Margin Width: OR

Treatment

Covariate

#

studies

1mm 2mm 5mm p-value

Endocrine Rx 16 1.0 0.98 0.90 0.95

Radiation

Boost

18 1.0 0.82 0.92 0.86

Meta-Analysis ResultsImpact of Margin Width on Local Recurrence

Adjusted for Treatment Covariates

SSO-ASTRO ConsensusThe Bottom Line

• A positive margin, defined as ink on invasive cancer or DCIS, is associated with at least a 2-fold increase in local recurrence

• Negative margins (no ink on tumor) optimize local control

• Wider margin widths do not significantly improve local control

• The routine practice of obtaining margins more widely clear than no ink on tumor is not indicated

SSO-ASTRO ConsensusThe Bottom Line

• The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multimodality therapy (which includes systemic therapy in most patients)

–is associated with low rates of local recurrence

–has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease healthcare costs

Do These Statements Apply to

Patient Subsets?

• Lobular carcinoma

• Age < 40

• Unfavorable biologic subtypes

• Extensive intraductal component (EIC)

Do These Statements Apply to

Patient Subsets?

• Lobular carcinoma

• Age < 40

• Unfavorable biologic subtypes

• Extensive intraductal component (EIC)

12

Page 12

• An EIC identifies cases that may have a large residual DCIS burden after lumpectomy.

Consensus StatementEIC

• An EIC identifies cases that may have a large residual DCIS burden after lumpectomy.

• There is no evidence of an association between EIC and an increased risk of LR when margins are negative.

• Margins wider than no ink on tumor are not routinely indicated.


• Given the potential for considerable residual DCIS in EIC+ patients, consider

• Post excision mammography to document complete removal of calcifications

• Other high-risk features, such as young age, multiple close margins

to identify patients likely to benefit from re-excision.


Practical Implications

• Consensus guidelines are intended to help standardize practice; not a substitute for clinical judgment


• Guideline intent

–To convey the view of the panelists that in current clinical practice where the vast majority of patients receive some form of systemic treatment, the frequent practice of routine re-excisions for arbitrary margin widths (2 mm, 5 mm, 10 mm, etc) intended to diminish local recurrence in the breast conservation therapy setting may not be evidence-based


• Provides the prospect for liberation from rules mandating re-excisions based merely on margin widths alone

• Suggests reserving re-excisions for individuals likely to be at high risk for local recurrence when all relevant risk factors are considered together

13

Page 13

SSO-ASTRO ConsensusEndorsed By

• Society for Surgical Oncology (SSO)

• American Society of Radiation Oncology (ASTRO)

• American Society of Breast Surgeons (ASBS)

• American Society of Clinical Oncology (ASCO)

St Gallen, 2015

NCCN Guidelines, 2016

February, 2014

What Does This Mean for Pathology Reporting of Margins?

• Consensus guidelines should influence how clinicians interpret our reports rather than how pathologists report margins

• Continue to report margins per CAP guidelines

–Positive margin = ink on invasive cancer or DCIS

–Report distance to negative margins in mm or fractions thereof for both invasive cancer and associated DCIS

Arch Pathol Lab Med 2015

14

Page 14

Conclusions

• While wider margins may have conveyed a small benefit in the past, multimodality therapy obviates the need for wider margins in contemporary practice

Conclusions

• The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multimodality therapy is associated with low rates of local recurrence and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease healthcare costs

JAMA Surgery, 2014

SNEAK PREVIEW

SSO-ASTRO-ASCO Consensus Guideline on Margins for DCIS

For pts with DCIS treated with excision and WBRT, the magic number is……

2 mm

The Future of Lumpectomy Margin Evaluation

• RF Spectroscopy/Electromagnetic response (MarginProbe)

• Spectral imaging

• Optical imaging

• High frequency ultrasound

• Molecular margins

4/7/2016

1

Spindle Cell Lesions of the Breast

Siobhan M. O’Connor, MD

April 16, 2016

I have no conflicts of interest to declare.

Outline

• Case

• Consensus review of phyllodes tumors

• Excluding metaplastic carcinoma

• Benign spindle cell lesions

• Malignant spindle cell lesions

Case

Case

• 59 year old female with left breast mass

• Mammography

• Mixed density mass composed of fat, pleomorphic and

dystrophic calcifications

• Developing asymmetry along the anterior aspect

measuring 5.4 cm x 4.2 cm x 3.9 cm

• Targeted ultrasound

• Mixed echogenic mass containing cystic and solid

components measuring 5.3 x 4.0 x 3.7 cm

• Central echogenic foci consistent with microcalcification

Core biopsy

Spindle cell proliferation

without epithelial

component

Mild cytologic atypia

4/7/2016

2

Case

• Core biopsy

• Cytokeratin AE1/AE3 negative

• HMWK negative

• S-100 negative

• Signed out as atypical spindle cell lesion

Excisional biopsy

Epithelial component

Leaf-like growth into

cystic spaces

Case

• Extensive stromal overgrowth and periductal

condensation

• Stromal atypia ranges from mild to severe

• Some areas of the tumor are well

circumscribed while others show infiltration into

surrounding breast tissue

• The mitotic count focally reaches 21 mitoses

per 10 high power fields

Case

• Excisional biopsy

• Malignant phyllodes tumor with associated

necrosis and calcifications

• 7.4 cm in greatest dimension

Consensus Review of Phyllodes Tumors

Tan PH et al. Histopathology 2016;68:5-21.

4/7/2016

3

Consensus Review Phyllodes Tumors

• Grading

• Fibroepithelial architecture with exaggerated

intracanalicular pattern with leaf-like fronds protruding

into cystic spaces

• Stromal hypercellularity

• Main feature distinguishing benign phyllodes tumor from

FA with prominent intracanalicular growth pattern is

increased stromal cellularity


Benign Borderline Malignant

Tumor border Well-defined

Well-defined,

may be focally

permeative

Permeative

Stromal cellularity

Cellular, usually

mild, non-uniform

or diffuse

Cellular, usually

moderate, non-

uniform or diffuse

Cellular, usually

marked & diffuse

Stromal atypia Mild or none Mild or moderate Marked

Mitotic activityUsually few

<5/10 HPF

Usually frequent

5-9/10 HPF

Usually abundant

≥10/10 HPFs

Stromal overgrowth AbsentAbsent, or very

focalOften present

Malig heterologous

elementsAbsent Absent May be present

Relative % PT 60-75% 15-20% 10-20%

WHO Criteria Distinguishing Benign, Borderline, Malignant PT

WHO Classification of Tumours of the Breast, 4th ed. 2012:145.


• Grading

• No objective criteria for separating minimal/mild from

moderate from marked stromal hypercellularity and

atypia

• Practical guide, start by centering on the most

cellular zones


• Mild

• Slight increase in cellularity

compared with perilobular stroma

• Evenly spaced nuclei, not touching or

overlapping

• Marked

• Confluent areas of densely

overlapping nuclei

• Moderate

• Intermediate findings with some

overlapping nuclei

• Mild stromal atypia

• Little variation in nuclear size

• Smooth nuclear contours

• Marked stromal atypia

• Marked variation in nuclear size

• Coarse chromatin

• Irregular nuclear membranes

• Discernible nucleoli

• Moderate stromal atypia

• Some variation in nuclear size

• Wrinkled nuclear contours


• Grading

• Application of guidelines can be filled with ambiguity

• Subjective how subdivisions of each parameter interact

to determine the final grade

• Not unusual for PTs to show intratumoral heterogeneity,

with features of benign, borderline, and malignant tumors

• Practical approach, call malignant if shows all

characteristics of malignancy, and borderline when not

all are present

• Also malignant if malignant heterologous element


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• Grading

• One study with 605 cases

• Stromal atypia, mitoses, overgrowth, and surgical

margins independently predict behavior

• Surgical margins most important



• Biological behavior

• Recurrence rate overall in literature

• Benign 10 to 17%

• Borderline 14 to 25%

• Malignant 23 to 30%




• Metastases and death always preceded by malignant

diagnosis

• Metastases invariably dismal prognosis with ensuing

death

• Suggests primary aim should be to recognize malignant

phyllodes tumors, for effective therapy to be

administered




• In a study of 335 PTs, metastases and death always

preceded by malignant diagnosis

• Rate of metastases ranges from 9.7 to 50% of malignant

tumors

• Metastases vanishingly rare in benign tumors

• Suggests diagnoses should focus on accurately

identifying malignant tumors



• Relationship between FA and PT

• Historically, PTs regarded as de novo lesions

• Number of studies have found highly recurrent mediator

complex subunit 12 (MED12) mutations in similar

proportions of FAs and PTs

• Evidence for direct evolution of PTs from FAs remains

limited

• But recent confirmation of linear progression in some cases



• Cellular FA versus benign PT

• Lawton et al, 21 cellular fibroepithelial lesions, evaluated

by 10 specialist breast pathologists

• Uniform agreement for only two cases

• Were selected from consultation cases, difficult lesions

over-represented

• Cellular FAs and benign PTs combined and compared to

borderline and malignant PTs

• Complete concordance in 53%

Lawton TJ et al. International J Surg Pathol 2014;22:695-698.


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• Important to keep in mind that FAs in pediatric age group

tend to have increased stromal cellularity

• And up to 7 mitoses per 10 HPFs have been reported

• In pediatric lesions, diagnosis of PT should only be made

in the presence of well-developed stromal fronds with

increased stromal cellularity

• In general, leafy architecture and increased stromal

cellularity should be used to discriminate between

cellular FA and benign PT




• Is it always necessary to distinguish benign PT from

cellular FA, given similar recurrence rates?

• WHO Working Group has suggested “benign

fibroepithelial neoplasm” for equivocal cases

• Recommend using term sparingly, as it does not represent

a new category

• Evidence that benign PTs may be treated less

aggressively




• Reported recurrence rate for benign PT ranges from 0 to

10.9%

• In two studies, no association with margin status

• Benign PT may be handled conservatively after excision,

even with positive margins

• Recurrence rate for malignant PT is 29.6% with

metastases and death in 22%

• Complete surgical excision needed for malignant PT



• Axillary lymph node dissection not recommended

• Adjuvant therapy

• Role of radiation therapy is controversial

• May reduce local recurrence, but no evidence of increased

overall survival

• No randomized controlled trials evaluating use of

adjuvant chemotherapy in malignant PTs



• Surgical margins

• Traditionally, management consisted of surgical excision

with wide margins, defined as at least 10 mm

• Limited data supporting a precise width of tumor-free

tissue which is significantly associated with reduced

tumor recurrence

• May be practical to consider tumor on ink, or <1 mm, as

positive margin

• Conservative approach to benign PT excised without

margins

• Recurrent and malignant PT should be excised with

negative margins


Metaplastic Carcinoma

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Metaplastic Carcinoma – Spindle Cell type

• Also known as sarcomatoid carcinoma and spindle cell

carcinoma

• Must always be excluded when atypical spindle cell

neoplasm encountered

• 0.25 to 1% invasive breast cancers

• Pure spindle cells or primarily spindle cells with minor

glandular, squamous, or heterologous elements

• Range from cytologically bland to markedly

pleomorphic

Mckinnon E, Xiao P. Arch Pathol Lab Med 2015;139:819-822.

Schnitt SJ. Surg Patho l2009:375-390


• Growth patterns

• Fascicular

• Fasciitis-like

• Storiform

• Haphazard

• Mitotic rate highly variable

• Usually infiltrative, but some show pushing border

Mckinnon E, Xiao P. Arch Pathol Lab Med 2015;139:819-822.

Schnitt SJ. Surg Patho l2009:375-390


• May need to perform panel of IHC

• IHC study of 20 pure sarcomatoid spindle cell

metaplastic carcinomas

• Pankeratin and basal cell keratins (K903, CK5/6,

CK14, CK17)

• 12 (60%) strong reactivity

• 6 (30%) weak or focal

• Myoepithelial markers (CD10, p63, SMA)

• 16 (80%) reactive for at least 2

• 3 (15%) reactive for one

Leibl S et al. Arch Pathol Lab Med 2005; 29:347-353.Schnitt SJ. Surg Pathol 2009:375-390.

Spindle Cell Carcinoma

Mitotic figure


• Low grade fibromatosis like carcinoma, or

metaplastic spindle cell carcinoma – fibromatosis-

like, deserves particular attention

• Proliferation of low grade, cytologically bland

spindle cells

• Squamous or glandular epithelial elements may be

admixed, but comprise <5% of tumor

• As name suggests, resembles fibromatosis

Dwyer JB, Clark BZ. Arch Pathol Lab Med 2015;139:552-557.

Infiltration into surrounding

breast tissue

Spindled to plumper round to

oval nuclei

Cytologically bland cells

Dwyer JB, Clark BZ. Arch Pathol Lab Med 2015;139:552-557.

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MSCC-FL

• Gross appearance is

infiltrative in 2/3 of cases

MSCC-FL

• Small disorganized

bundles of spindle cells

Brogi E. Seminars Diagn Pathol 2004;21:57-64.

MSCC-FL

• Minute clusters of epithelioid spindle cells on H&E

and with K903


Benign Spindle Cell Lesions

Pseudoangiomatous Stromal Hyperplasia (PASH)

• Incidental finding in ~23% of breast biopsies

• Most common in premenopausal women

• Frequent component of gynecomastia

• Tumor forming PASH almost exclusively in women

• When symptomatic, presents as a firm, non-tender,

unilateral mass


Virk RK, Khan A. Arch Pathol Lab Med 2010;134:1070-1074.

PASH – Imaging and Gross Features

• Mammography

• Well circumscribed round to oval density without

calcification

• Ultrasound

• Solid hypoechoic mass

• Circumscribed, non-encapsulated mass

• 1 to 15 cm in greatest dimension

• Homogeneous or lobulated tan-pink to yellow cut

surfaceBrogi E. Seminars Diagn Pathol 2004;21:57-64.


PASH, Circumscribed

and lobulated

PASH, Circumscribed

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PASH – Microscopic Features

• May occur as isolated mass or coexist with any breast lesion

• Slit-like anastomosing spaces

• Lined by flat, elongated myofibroblasts

• Separated by bands of eosinophilic hyalinized tissue

• Myofibroblasts with scant cytoplasm and small, bland nuclei

• Usually involves interlobular stroma, but may also involve intralobular



PASH

• Fascicular PASH

• More pronounced proliferation of myofibroblasts

forming distinct bundles

• If mass-forming, DDx is myofibroblastoma

Images – www.rosenbreastpathology.com -- image bank

PASH – Immunohistochemistry

• Myofibroblasts show strong reactivity for vimentin

• CD34 positive in the majority of lesions

• Negative for cytokeratin and vascular markers

• Sometimes reactive for PR

• ER usually negative, but sometimes weak

reactivity


PASH – Treatment

• No treatment required unless mass-forming

• Ipsilateral recurrences have been reported,

but uncommon

• Recurrent lesions behave in a benign fashion

and can be managed with re-excision



Fibromatosis

• May occur at any age after adolescence

• Most common between 20 and 40 years

• Rarely seen in men

• Gardner’s syndrome

• Rarely associated with familial adenomatous

polyposis

• Role of trauma is controversial


http://www.rosenbreastpathology.com

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Fibromatosis – Presentation and Imaging

• Presents as firm palpable mass

• May cause cutaneous or nipple retraction

• Mammography

• Mass or area of architectural distortion

• Usually devoid of calcifications


Schnitt SJ. Surg Pathol 2009:375-390.

Fibromatosis – Gross Features

• Ill-defined or stellate mass

• Suggestive of invasive carcinoma

• White-gray cut surface and scar-like consistency

• 1 to 10 cm, with average 2.8 cm



Fibromatosis, stellate focus

Stellate image – www.rosenbreastpathology.com -- image bank

Rounded image - Brogi E. Seminars Diagn Pathol 2004;21:57-64.

Fibromatosis, rounded focus

Fibromatosis – Microscopic Features

• Long sweeping fascicles of myofibroblasts which

infiltrate into breast parenchyma

• Cellularity ranges from low to focally moderate

• Collagen fibers intervene among myofibroblasts

• Spindle cells have scant cytoplasm, open chromatin,

and inconspicuous nucleoli

• Lymphoid infiltrates common, especially at periphery

• Mitotic figures usually not present, but may be seen

• May be numerous focally



Fibromatosis

Long fascicles

Infiltration into fat

Peripheral lymphoid aggregates

Fibromatosis -- Immunohistochemistry

• Cells are strongly positive for vimentin

• Virtually never positive for CD34

• Reactive for smooth muscle actin

• May be reactivity for desmin and S-100, but

usually in minority of cells

• ~75% positive for β-catenin, nuclear pattern

• Not specific and may be seen in a minority of

spindle cell carcinomas and in FAs, PTs


Schnitt SJ. Surg Pathol 2009:375-390


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CD34

β-catenin

Fibromatosis – Treatment

• Locally aggressive, wide local excision recommended

• Because ill-defined borders, difficult to judge adequacy

of margins during surgery

• Local recurrence in 21% to 27%

• Risk higher with positive margins

• But reported in cases with negative margins

• Most within 3 years of diagnosis

• Cellularity, mitotic activity, pleomorphism not helpful in

predicting recurrence

Gump FE et al. Surg Gynecol Obstet 1981;15:57-60.

Rosen PP, Ernsberger D. Cancer 1989;63:1363-1369.

Wargotz ES et al. Am J Surg Pathol 1987;11:38-45.

Fibromatosis – Treatment

• Radiotherapy has been used in non-mammary

fibromatosis, but not established in mammary

fibromatosis

• Chemotherapy has been used for deep non-mammary

fibromatosis

• May be considered in primary or recurrent mammary

type with unresectable invasion of chest wall, axilla, or

supraclavicular

• Effect of anti-estrogen therapy in mammary

fibromatosis not well-documented

Okuna SH, Edmonson JH. Cancer 2003;97:1134-1135.

Patel SR et al. Cancer 1993;72:3244-3247.

Fibromatosis – Differential Diagnosis

• MSCC-FL

• Greater nuclear atypia and higher mitotic rate (also in

low grade sarcoma)

• Desmoid-like foci and peripheral lymphoid aggregates

suggest fibromatosis

• Cytokeratins and myoepithelial markers negative in

fibromatosis

• Previous surgical site changes, trauma

• Fat necrosis, multinucleated giant cells, hemosiderin

deposition favor reactive/reparative process




Fibromatosis – Differential Diagnosis

• Nodular fasciitis

• Inflammatory cells dispersed more diffusely at

periphery and within the lesion in nodular

fasciitis

• Inflammation in fibromatosis usually isolated

lymphoid aggregates at periphery of lesion

• Higher mitotic activity in nodular fasciitis


Wargotz ES et al. Am J Surg Pathol 1987;11:38-45.

Nodular Fasciitis

• Uncommon in breast

• Subcutaneous tissue or parenchyma

• Rapidly growing mass that may be painful or tender

• Disappears spontaneously within a few months



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• Mammography

• Usually mimics a fibroadenoma, but can

simulate an invasive carcinoma

• Unencapsulated mass

• Pink-grey, mucoid cut surface

Nodular Fasciitis – Imaging and Gross Features


• Generally well-circumscribed, but may simulate

invasion into adjacent tissue focally

• Plump spindle cells arranged in short fascicles and

whorls

• Stroma typically loose, myxoid, may show cystic

change

• Likened to fibroblasts growing in tissue culture

• Extravasated RBC and mixed inflammatory infiltrates

common

Nodular Fasciitis – Microscopic Features



• Mitotic figures readily identified and may be numerous, but

nuclear atypia and necrosis usually absent

• Early lesions highly cellular; regressing less cellular with

more stromal collagen

• Usually displaces adjacent breast ducts and lobules

• Myofibroblasts express smooth muscle actin, but may be

focal

• Desmin expression occasionally seen, and generally focal

Nodular Fasciitis – Microscopic Features & IHC



Relatively well circumscribed

Short bundles

Plump myofibroblasts

Dispersed inflammation

Mitotic figures

• Will usually spontaneously regress, but biopsy or

excision almost always performed due to growing

mass

• Local excision is adequate treatment

Nodular Fasciitis – Treatment


• Fibromatosis – addressed previously

• Metaplastic carcinoma

• Myoepithelial/epithelial markers positive in

metaplastic carcinoma

• Inflammatory cells in nodular fasciitis

• Nodular fasciitis non-invasive

Nodular Fasciitis – Differential Diagnosis


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Myofibroblastoma

• Thought to occur more frequently in men

• Identified in greater numbers on screening

mammography

• Now appear to occur with equal frequency in

men and women

• More common after 50 years old



Myofibroblastoma – Imaging and Gross Features

• Mammography

• Homogeneous, lobulated, well-circumscribed, lacks

calcifications

• Ultrasound suggests fibroadenoma

• Ranges from 1 to 12 cm

• Circumscribed and rubbery

• Grey-white cut surface with areas of fat

• Lacks a true capsule

• May have pseudocapsule consisting of compressed

breast tissueBrogi E. Seminars Diagn Pathol 2004;21:57-64.

Myofibroblastoma

• Well-circumscribed, fleshy, and lobulated

Stellate image – www.rosenbreastpathology.com -- image bank

Myofibroblastoma – Microscopic Features

• Uniform and slender myofibroblasts

• Arranged in short, intersecting fascicles

• Intervening thick bands of brightly eosinophilic collagen

• Nuclear atypia absent or minimal

• Mitoses uncommon, rarely up to 1 to 2 mitoses/10 HPF

• Adipocytes intrinsic component

• Expansile growth and usually does not contain

entrapped ducts

• Infiltrative variant has been identified



Haphazard arrangement

Short fascicles

Thick collagen bundles

Myofibroblastoma, classic type

Well circumscribed

Intrinsic adipocytes

Myofibroblastoma -- Immunohistochemistry

• Immunoreactive for CD34, bcl-2, CD99, vimentin

• Can be positive for desmin, smooth muscle actin,

and, focally, h-caldesmon

• Expression of ER and PR in 70% to 90% of cells in

nearly all cases

• Negative for cytokeratins, S-100, and myoepithelial

markers




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Desmin

SMA

ER

Myofibroblastoma -- Variants

• Collagenized or fibrous

• Epithelioid

• Cellular

• Infiltrative

• Myxoid


Magro G. Histol Histopathol 2015;31:1-23.


• Myofibroblastoma, collagenized

• Tumor cells embedded in

collagenous stroma

• May resemble fascicular PASH

Images – www.rosenbreastpathology.com -- image bank Images – www.rosenbreastpathology.com -- image bank

• Myofibroblastoma, epithelioid

• Arranged in alveolar groups

• Myofibroblastoma, epithelioid

• Linear pattern reminiscent of

lobular carcinoma


• Myofibroblastoma, cellular

• Dense proliferation of

spindle-shaped cells

• Collagenous bands may

be absent in some areas


• Myofibroblastoma, Infiltrative

• Characterized by invasive

growth

• Fat, stroma, ducts, and

lobules incorporated





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Myofibroblastoma – Differential Diagnosis

• Sarcoma and metaplastic carcinoma usually more

cellular with frequent mitoses

• Fasciitis and fibromatosis also contain

myofibroblasts, but tend to be stellate and

infiltrative

• Plump myoid cells and inflammation of fasciitis not

seen in myofibroblastoma

• Fibromatosis shows abundant collagen and spindle

cells arranged in broad bands rather than short

fascicular clusters

Myofibroblastoma -- Treatment

• No recurrences have been reported

• Almost all managed adequately by excisional

biopsy

• Complete excision recommended when

encountered in core


Malignant Spindle Cell Lesions


• Most commonly, represent spindle cell carcinoma or

stromal component of malignant phyllodes

• Primary sarcomas of the breast are extremely rare

• Comprise <0.1% of malignant breast tumors

• Angiosarcoma is the most common primary breast

sarcoma

• Differentiated from other sarcomas based on vascular

morphology and vascular immunohistochemical

markers

Adem C. Brit J Cancer 2004;91:237-241.




• In a series from Mayo Clinic with review of literature

• 25 patients ranging in age from 24 to 81 years

• 6 each fibrosarcoma, angiosarcoma, and pleomorphic sarcoma

• 3 myxofibrosarcomas

• 2 leiomyosarcomas

• 1 each hemangiopericytoma and osteosarcoma

• Tumor size ranged from 0.3 to 12 cm (mean 5.7 cm)

• Local recurrence was seen in 11 patients and distant

metastasis in 10 patients

• Morphologically similar to extramammary sarcomas

Adem C. Brit J Cancer 2004;91:237-241.

In Summary

• Spindle cell lesions of the breast represent a wide

spectrum of reactive and neoplastic processes

• Critical to exclude metaplastic carcinoma

• Excisional biopsy is often required for accurate diagnosis

• Immunohistochemical stains may be useful in

morphologically challenging cases

• Primary sarcomas of the breast are extremely rare, and

malignant spindle cell lesions are more likely to represent

metaplastic carcinoma or stromal component of malignant

phyllodes

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End!

QUESTIONS?

1

Page 1

Case Presentations

Stuart J. Schnitt, M.D.Beth Israel Deaconess Medical Center and

Harvard Medical School,Boston, MA

Disclosures

• None

Case 1

• May, 2005:

–A 68 year old woman was found to have left breast mass in the 2:00 position on a screening mammogram.

–An ultrasound-guided core needle biopsy was performed and a diagnosis of ductal carcinoma in situ was rendered at an outside hospital.

• June, 2005:

–A surgical excision was subsequently performed at the outside hospital

–Slides of the core needle biopsy and excision sent to BIDMC for consultation.

2

Page 2

Excision SpecimenGross Examination

• 7 x 4.7 x 2 cm fibrofatty specimen containing a firm, relatively circumscribed mass measuring 0.9 cm

3

Page 3

This is really weird!

Approach to a breast tumor that looks really weird

• Is it an unusual variant of a common breast lesion?

• Is it an uncommon breast lesion?

• Is it a skin lesion involving the breast?

• Is it a metastasis from an extra-mammary site?

What can we say for sure?

• Nested pattern of epithelial cells with fibrovascular stromal cores; some cores have foamy histiocytes

• Growth pattern worrisome for invasion

• Cells have columnar shape, eosinophilic cytoplasm and abnormal position of nuclei (toward apex rather than base of cells)

Is it invasive?

4

Page 4

SMMHC CALP

p63Is it invasive?

• Sure looks that way on both morphology and myoepithelial cell immunostains

What is the immunophenotypeof the cells?

CK7

5

Page 5

CK5/6 GCDFP

MMG ER

Other Markers

• PR negative

• HER2 negative

• CK20 negative

• TTF-1 negative

• Thyroglobulin negative

What is the immunophenotypeof the cells?

• It’s as weird as the morphology!

–Cells are cytologically low grade and express luminal cytokeratins

–But, cells also express basal cytokeratinsand are ER negative

–Stain at least focally for GCDFP and mammaglobin consistent with breast origin

6

Page 6

• ?Skin appendage or salivary gland-like features

Outside Expert Opinions

1. Expert in analog lesions:

Low-grade invasive adenocarcinomawith cutaneous adnexal analog features (based largely on strong CK5/6 expression)

2. Breast expert:

Intraductal carcinoma with adnexalanlage features (acknowledged lack of myoepithelial cells but didn’t care about it)

Then, in 2007………

Case History2007 Case

• 62 year old woman with new 9 mm mass on screening mammogram

• Core needle biopsy reported as showing DCIS

• Excisional biopsy performed

7

Page 7

Still didn’t know what it was but I knew immediately that I

had seen another case before!

Outside Expert Opinion

• Sent 2007 case and 2005 case (again) to same expert breast pathologist

• Dx for 2007 case: “Solid papillary intraductal carcinoma with adnexalanlage features”

• This lesion and the 2005 lesion “are unique in my experience”.

What happened next?

• Since 2007, 11 more cases (total of 13)

• All females

• Median age 65 years (range 51-79 years)

• Mammographic mass or density

–Median size 0.9 cm (range 0.6-1.5 cm)

Solid Papillary Carcinoma with Reverse Polarization

(SPCRP)

Solid Papillary Carcinoma with Reverse Polarization (SPCRP)

• Solid, circumscribed nodules, many with fibrovascular cores (solid papillary pattern)

• Haphazard distribution of nodules between normal ductal-lobular structures and extending into fat

• Collagenous stroma with little or no desmoplasia

• Foamy histiocytes within fibrovascular cores

Key Histologic Features

8

Page 8

• Columnar epithelial cells with eosinophiliccytoplasm

• Nuclei with low to intermediate grade atypia and occasional grooves and intracytoplasmic inclusions (prominent in only 1 case)

• Nuclei present in non-basal location (apparent reversal of normal polarity)


Key Histologic Features

• Jigsaw pattern of cell nests

–Present to some degree in all cases

–Prominent in one case

Less Frequent Histologic Features


9

Page 9

• Jigsaw pattern of cell nests

–Present to some degree in all cases

–Prominent in one case

• Frankly papillary areas

–Present in 5/12 cases (42%)

Less Frequent Histologic Features


Immunophenotype


• No myoepithelial cells around tumor nodules in any case

• Positive for low AND high molecular weight cytokeratins

• GCDFP and mammaglobin each positive in ~60%

• All cases negative for TTF-1 and thyroglobulin

Immunophenotype


• 62% entirely ER negative; remainder low ER positive (1-10%)

• 15% PR positive

• All cases HER2 negative

• AR focally positive in 1 case

• Low proliferation rate by Ki67 (<5%)

• Rich vascular network around nests on CD31 and CD34 stains

10

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Immunophenotype


• E-cadherin: Strong lateral membrane staining

• MUC1: Apical membrane staining seen on ends of cells closest to nucleus (reverse polarity)

ER

ER Ki67

CD31

E-cad MUC1

11

Page 11

Solid Papillary Carcinoma with Reverse Polarization

Genomic Alterations (in collaboration with John Iafrate and Jorge Reis-Filho)

• IDH2 mutations in 10/13 cases (77%)

–Not previously reported in breast cancers

• 8 concurrently displayed mutations in PI3 kinase pathway (PIK3CA or PIK3R1)

• Functional studies

– IDH2 and PIK3CA mutations appear to be driver alterations resulting in reverse polarization phenotype

Clinical Course

• Mastectomy (3 pts); excision/lumpectomy +/- XRT (8 pts); unknown (1 pt)

• Sentinel lymph node biopsy (6 pts): All node negative

• Among 7 pts with f/u, all NED (median 31 months; range 12-77 months)

Conclusions

• Solid papillary carcioma with reverse polarization (SPCRP) represents a histologically low grade breast carcinoma with distinctive morphologic, immunophenotypic and genotypic features

Conclusions

• Appears to be the same lesion previously described as “breast tumor resembling the tall cell variant of papillary thyroid carcinoma”, but–No staining for thyroglobulin or TTF-1

–No BRAF mutations

–Distinct mutational profile (IDH2 mutations)

–Unrelated to thyroid carcinomas

–Solid papillary carcinoma with reverse polarization (SPCRP) preferred term

Case 1

DIAGNOSIS

Solid papillary carcinoma with

reverse polarization (SPCRP)

12

Page 12

Case 2

• A 43 year old woman was found to have a mass on a screening mammogram

• A core needle biopsy was performed

Diagnosis

Invasive Lobular Carcinoma

ER PR

13

Page 13

Diagnosis

Invasive Lobular Carcinoma,ER+, PR+, HER2-

• Mastectomy recommended

• Patient came to BIDMC BreastCare Center for second opinion

• Slides brought along for review

KER

Actin

Desmin

bcl2

CD34

Diagnosis

Myofibroblastoma, epithelioid variant

14

Page 14

MyofibroblastomaClinical Features

• Males = females• Increasingly detected on

mammogram• Peak 50-75 years• Mobile, slowly growing• Most < 4 cm; occasionally very

large• Also may occur outside breast

• Benign; no recurrence

MyofibroblastomaPathologic Features

• Rubbery firm, lobulated mass; cut surface homogenous gray to pink whorled or lobulated tissue

• Classic type-histology: –Circumscribed, no true capsule

–Variable amounts of fat

–Short fascicles of uniform spindle-shaped cells with round to oval nuclei

–Broad bands of hyalinized collagen

MyofibroblastomaPathologic Features

• Rubbery firm, lobulated mass; cut surface homogenous gray to pink whorled or lobulated tissue

• Classic type-histology: –Circumscribed, no true capsule

–Variable amounts of fat

–Short fascicles of uniform spindle-shaped cells with round to oval nuclei

–Broad bands of hyalinized collagen

15

Page 15

MyofibroblastomaOther Histologic Features

• Usually no entrapped mammary ducts/lobules

• Perivascular lymphoplasmacytic infiltrates

• Mast cells

• Myxoid change

• Chondroid or smooth muscle metaplasia

MyofibroblastomaImmunophenotype

• Cells positive for–Vimentin

–CD34 (epithelioid variant may be negative)

–ER

–PR

–AR

–Actin

–Desmin

– bcl2

• Staining may be focal / variable

MyofibroblastomaVariants

• Collagenized/fibrous

• Cellular

• Myxoid

• Lipomatous

• Infiltrative

• Atypical

• Deciduoid

• Epithelioid

Collagenized/Fibrous

Collagenized/Fibrous Cellular

16

Page 16

Cellular Myxoid

Lipomatous Lipomatous

Epithelioid Variant of Myofibroblastoma

• Polygonal or epithelioid cells arranged in cords or alveolar groups

• May constitute predominant growth pattern or be admixed with classic form

• Growth pattern may resemble invasive lobular carcinoma

Myofibroblastoma Lobular Carcinoma

17

Page 17

MyofibroblastomaAdditional Pearls

• Cases with atypia/pleomorphism

– ?clinical significance

• Similar lesions at extramammarylocations, especially inguinal

• Relationship to spindle cell lipoma

• Morphologic and immunophenotypic overlap

• “13q/Rb family of tumors”: deletion or rearrangement of 13q14 with loss of Rbexpression by IHC

Myofibroblastoma Spindle Cell Lipoma

MyofibroblastomaDifferential Diagnosis

Reactive/benign

spindle cell lesions

•Nodular fasciitis

•Spindle cell lipoma

•Solitary fibrous tumor

•Nerve sheath tumors

•Smooth muscle tumors

•PASH

Spindle cell

sarcomas

Carcinomas

•Metaplastic

•Lobular

Pseudoangiomatous Stromal Hyperplasia

(PASH)

• Primarily pre-menopausal women

• Most commonly seen as incidental microscopic finding (~25% of breast specimens)

• Tumor-forming PASH– circumscribed mass with smooth external surface

– homogeneous tan, gray, or white cut surface

Pseudoangiomatous Stromal Hyperplasia

(PASH)

• Slit-like, often anastomosing spaces in dense collagenous stroma

• Myofibroblasts present at edges of spaces may resemble endothelial cells–Positive for vimentin, CD34, actin, desmin

–Often positive for PR, but usually ER negative

• Must be distinguished from vascular lesions, esp. angiosarcoma

18

Page 18

Fascicular PASH

• Myofibroblasts in distinct fascicles in background of conventional PASH

• Most extreme examples have growth pattern similar to myofibroblastoma

19

Page 19

Spectrum of Myofibroblastic Lesions

PASHMyo-

fibroblastoma

Fascicular

PASH

Diagnosis

Myofibroblastoma, epithelioid variant

(confirmed on subsequent excision)

4/7/2016

1

CAP Economic Affairs Update

North Carolina Society of Pathologists

Diana M. Cardona, MD, FCAP

Associate Professor of Pathology, Duke Medicine

Chair, CAP Economic Affairs Measure and Performance

Assessment Sub-committee

April 16, 2016

Today’s Agenda

• Medicare Fee Schedule Changes

– CMS’ 2016 Physician Fee Schedule Final Rule

• Current Pay for Performance Programs

• MACRA –

– Medicare Access and CHIP Reauthorization Act

• PAMA –

– Protecting Access to Medicare Act

© 2016 College of American Pathologists. All rights reserved.

Payment for Pathology Services


Specialty Allowed

Charges

(millions)

Impact of

Work RVU

Changes

Impact of

PE RVU

Changes

Impact of

MP RVU

Changes

Combined

Impact

Pathology $1,330 4% 4% 0% 8%

Independent

Laboratory

$834 1% 7% 0% 9%

*Does not equal sum of RVU columns due to rounding.

• Reflect averages by specialty (based on Medicare utilization)

• For individual physicians and practices, the impact depends on

mix of services and payers (Medicare and non-Medicare)

• Physicians receive pay from other Medicare payment systems

o For instance, independent laboratories receive 83% of

their Medicare revenue from CLFS


• CMS finalized partial increases

– Immunohistochemistry

– In situ hybridization

• CMS implemented proposed payment update

• CMS accepted some of the AMA/RUC

recommendations

• CMS implemented cuts to prostate biopsy services


Prostate Biopsy Services

• In 2009, CMS created four G codes for the surgical

pathology of prostate saturation biopsy services.

• In 2015, CMS required one code for all prostate

biopsy specimens regardless of the number of

specimens or technique used to obtain the biopsy.

– G0416- CMS stated this simplified the coding and

mitigated overutilization incentives.

• 2015 final rule added service to misvalued code list


Prostate Biopsy Services


• The AMA RUC evaluated TC and PC values

• TC reduced due to alignment of direct inputs to

updated 88305 value

• Shifts in medical service volume and reporting

specialties contributed to PC decline

• TC cuts are phased in over two years CMS

• Updated PC values anticipated in 2017

CPT Code MOD DESCRIPTOR

2015

Payment

2016

Payment

Percentage

Change

G0416 Prostate biopsy, any mthd $649.32 $533.84 -17.8%

G0416 26 Prostate biopsy, any mthd $182.90 $158.00 -13.6%

G0416 TC Prostate biopsy, any mthd $466.42 $375.83 -19.4%

4/7/2016

2

Payment for Pathology Add-on Services


CPT

Code DESCRIPTION

Work

RVU

2015

Work

RVU

2016

Change

in Work

RVU

Percentage

Change in

Work RVU

88350 Immunofluor addl antibody stain NA 0.56 NA NA

88341 Immunohisto addl antibody slide 0.42 0.53 0.11 26%

88364

In situ hybridization addl

probe(fish) 0.53 0.67 0.14 26%

88369

M/phmtrc alys ish quant/semiq

addl probe 0.53 0.67 0.14 26%

Payment for Immunohistochemistry


CPT

Code MOD DESCRIPTION

2015

Payment

2016

Payment

Percentage

Change

88341 Immunohisto addl antibody slide $67.91 $90.64 34%

88341 26 Immunohisto addl antibody slide $21.92 $27.95 28%

88341 TC Immunohisto addl antibody slide $45.99 $62.70 36%

88342 Immunohisto initial antibody stain $90.91 $107.48 18%

88342 26 Immunohisto initial antibody stain $36.65 $37.26 2%

88342 TC Immunohisto initial antibody stain $54.26 $70.22 29%

88344 Immunohisto per specim multiplex $117.50 $173.77 48%

88344 26 Immunohisto per specim multiplex $40.25 $40.84 2%

88344 TC Immunohisto per specim multiplex $77.26 $132.92 72%

Payment for In Situ Hybridization

CPT


2015

Payment

2016

Payment

Percentage

Change

88368 Insitu hybridization manual $109.24 $115.01 5%

88368 26 Insitu hybridization manual $41.32 $41.20 0%

88368 TC Insitu hybridization manual $67.91 $73.81 9%

88369

M/phmtrc alys ish quant/semiq addl

probe $74.02 $108.56 47%

88369 26


probe $25.15 $31.89 27%

88369 TC


probe $48.87 $76.67 57%

88377 M/phmtrc alys ishquant/semi multiplex $214.88 $412.02 92%

88377 26 M/phmtrc alys ishquant/semi multiplex $65.76 $66.28 1%

88377 TC M/phmtrc alys ishquant/semi multiplex $149.12 $345.74 132%




CPT


2015

Payment

2016

Payment

Percentage

Change

88184 Flowcytometry/ tc 1 marker $94.51 $76.31 -19%

88185 Flowcytometry/tc add-on $57.49 $46.22 -20%

88312 Special stains group 1 $98.10 $98.89 1%

88312 26 Special stains group 1 $28.03 $28.30 1%

88312 TC Special stains group 1 $70.07 $70.58 1%

88313 Special stains group 2 $68.27 $69.15 1%

88313 26 Special stains group 2 $12.58 $12.54 0%

88313 TC Special stains group 2 $55.70 $56.61 2%

88314 Histochemical stains add-on $75.10 $78.10 4%

88314 26 Histochemical stains add-on $23.00 $23.29 1%

88314 TC Histochemical stains add-on $52.10 $54.82 5%

Misvalued Code Initiative

• CMS will examine potentially misvalued services

– This may include physician work surveys, data collection,

research, and/or analyses

– CMS also may use analytic contractors


Code Short Description

10022 Fna w/image

36516* Apheresis selective

38221 Bone marrow biopsy

88185 Flowcytometry/tc add-on

88189 Flowcytometry/read 16 & >

88321 Microslide consultation

88360 Tumor immunohistochem/manual

88361 Tumor immunohistochem/comput

PQRS and VBM: Background

Physician Quality Reporting System (PQRS)

A quality reporting program that provides payment adjustments to Medicare Part B reimbursement to eligible professionals based on whether or not they satisfactorily report data on quality measures for covered services.

Value-Based Payment Modifier (VBM)

A budget neutral payment adjustment applied to Medicare Part B reimbursement to a group based on the cost and quality of services provided to Medicare patients.

4/7/2016

3

Pathology Measures

• Breast Cancer Resection Pathology Reporting

• Colorectal Cancer Resection Pathology Reporting

• Barrett’s Esophagus

• Radical Prostatectomy Pathology Reporting

• Immunohistochemical (IHC) Evaluation of HER2 for

Breast Cancer Patients

• Lung cancer reporting (biopsy/cytology specimens)*

• Lung cancer reporting (resection specimens)*

• Melanoma reporting*


Quality Reporting Initiatives

• 2016 PQRS will affect 2018 PQRS, VBM penalties

– Separate -2% penalty under PQRS program

– +/- 4% VBM adjustment for physicians in groups 10 or more

– +/- 2% VBM adjustment for solo physicians, groups 2-9

• VBM will apply to all physicians

• Successful PQRS participation in 2016 will stop the

2018 PQRS penalty and automatic VBM penalty.



• VBM score is a calculation based on performance

of the Group (defined by tax identification number

(TIN))

– Quality performance

– Cost measures, which are based on the total cost of care

attributed to the primary care physician

– For pathology, we are considered to be average cost

providers because we do not provide primary care

services


• All Physicians are Subject to Quality Tiering


Successful PQRS Participants in groups of 10 or more

Quality/Cost Low Cost Average Cost High Cost

High Quality +4.0x* % +2.0x* % +0.0%

Average Quality +2.0x* +0.0% -2.0%

Low Quality +0.0% -2.0% -4.0%


• Ways to participate in 2016 PQRS

– Individuals can report via claims or registry

– Group practices can report via group practice reporting

option (GPRO) registry or GPRO web interface

• A 2018 PQRS penalty of -2% will be applied to

those unsuccessful in the 2016 PQRS program

– Individuals who are unsuccessful also face an automatic

2 to 4% VBM penalty

Quality Reporting Initiatives Final Highlights

• CMS clarified pathologists billing from independent

laboratories (POS 81) are not subject to PQRS/VBM

payment adjustments.

• PQRS and VBM programs expire after 2018 and are

replaced by the new Merit-Based Incentive

Payment System (MIPS).


4/7/2016

4

Medicare Access and CHIP

Reauthorization Act (MACRA)

• Replaces the SGR with two payment pathways:

– Merit-Based Incentive Payment System (MIPS)

– Alternative Payment Models (APMs)

• Future payment updates under MIPS are tied to:

– Quality performance metrics (formerly PQRS)

– EHR Meaningful Use

– Resource utilization (formerly VBM)

– Clinical Practice Improvement Activities

• Effective 2019 based on 2017 performance

© 2016 College of American Pathologists. All rights reserved. Source: Centers for Medicare & Medicaid

Services

MACRA-MIPS

MACRA-MIPS Potential Impact of MIPS on Pathology


Year ProgramPossible

Penalty

Total With

Full Penalty

(millions)

Projected

Total(millions)

Total with

Full Bonus(millions)

Possible

Bonus

Difference

Full Penalty and Full

Bonus

(millions)

2019 MIPS -4% $ 2,169 $ 2,224 $ 2,279 4% $110

2020 MIPS -5% $ 2,180 $ 2,251 $ 2,321 5% $141

2021 MIPS -7% $ 2,176 $ 2,277 $ 2,378 7% $ 202

2022 MIPS -9% $ 2,171 $ 2,304 $ 2,437 9% $ 266

2023 MIPS -9% $ 2,195 $ 2,331 $ 2,467 9% $ 272

2024 MIPS -9% $ 2,218 $ 2,358 $ 2,497 9% $ 278

2025 MIPS -9% $ 2,242 $ 2,384 $ 2,526 9% $ 284

Total Impact on Pathology Specialty 2019-2025 $1.5 billion

*Projections based on ten previous years of Medicare spending

**All dollar figures listed in $ millions

What is an eligible APM?

• A model under the Center for Medicare and

Medicaid Innovation (CMMI)

• Medicare Shared Saving Program ACO

• A Health Care Quality Demonstration project

• APMs base payment on quality measures

comparable to those under MIPS

• Require certified EHR technology

• Either bear more than nominal financial risk OR are

a medical home under CMMI© 2016 College of American Pathologists. All rights reserved.

4/7/2016

5

Qualifying for APM Bonuses

Year

Medicare Only, %

Payments in An Eligible

APM

All Payer, % of

Payment in An Eligible

APM

2019-2020 25% Not applicable

2021-2022 50% 25% Medicare

50% all payer

2023-2024 75% 25% Medicare

75% all payer

2025 and beyond 75% 25% Medicare

75% all payer


Qualifying physicians (QPs) in eligible APMs are

excluded from MIPS and receive annual 5% bonuses for

2019 through 2024. In 2025, bonuses drop to 0.75% vs.

0.25% for non-QPs.

MIPS: Pathologists Face Hurdles

50% PQRS

• Eight measures continued through 2016 but high

performance may lead to discontinuation by CMS.

10% Resource Use

• Value-Based Modifier (VBM) program is designed

for primary care specialties and generally does not

measure the value that pathologists provide to

their patients.

15%

Clinical

Practice

Improvement

Activities

• CAP has suggested activities that pathologists

could successfully report.

25%Meaningful

Use

• CAP has secured relief from MU penalties through

2016, but it is not known how CMS will score

pathologists on this category.


CAP Economic Affairs Committee (EAC) has formed a

Special MACRA Workgroup

• Ensure pathologists can comply with MIPS

• Engaging CMS on defining metrics that could get

pathologists credit for clinical improvement activities

• Preparing members who opt for APM participation

• Proposed rule for MACRA expected in spring 2016

• Stay tuned to future updates on MACRA through

STATLINE and upcoming webinar.


Protecting Access to Medicare Act

(PAMA)

• Implementation of PAMA

• Establishes reporting requirements for labs, data

used to set reduced CLFS reimbursements:

o 10% 2017–2019

o 15% 2020–2022

• CMS issued a delayed proposed rule on September

25, 2015

• Final rule, by statute, is overdue

• CAP calling for data collection and data submission

deadline extensions


Implementation of PAMA

CAP is advocating with CMS on PAMA:

• Scope of entities required to submit data must be

broadened

• Proposed limited scope of reporting entities

reduces low expenditure threshold and revises

majority of revenue definition based on Medicare

lab revenues rather than Medicare revenue from

the entire organization

• More specifics needed on reporting requirements


Keep Informed…

• On the latest Advocacy efforts through STATLINE

weekly issues and special alerts

• With webinars throughout 2016 on:

– Final PAMA regulation

– FDA guidance on LDT oversight

– 2017 Medicare Physician Fee Schedule

– Other emerging issues

• By attending the CAP Policy Meeting


4/7/2016

6

2016 CAP Policy Meeting

• May 2-4 in Washington, DC

– Register at CAP.org

• Receive insights from CMS and FDA officials and

health policy leaders

– e.g. Panel on MACRA, MIPS, APMs

– Keynote speakers: David Gregory and Harold Miller

• Engage with members of Congress during the

CAP’s Annual Hill Day


Questions?


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