Breast Pathology Cases Regional Training Day April 2017Breast Pathology Cases Regional Training Day April 2017 Dr Claire Murray Consultant Histopathologist Royal Devon and Exeter Hospital

Breast Pathology Cases Regional Training Day

April 2017

Dr Claire Murray

Consultant Histopathologist

Royal Devon and Exeter Hospital

Case 1(14/604)

• 28 year old female

• Left breast lump

• Well-defined 50 mm mass

• Fatty in texture and easily enucleated at surgery

• Excision specimen

Case 1 Macro

Case 1. Diagnosis

Hamartoma (adenolipoma)

Breast Hamartoma - Clinical

• Occur at any age but most common in premenopausal women

• Present as well circumscribed mass clinically and radiologically

• Vary between 10 and 80mm in size

Breast Hamartoma - Histology

• Well circumscribed, round or oval mass • Surrounding compressed breast tissue forms

pseudocapsule • Disordered ducts and lobules within lesion are typically

normal • May be associated with fibrocystic change • May contain smooth muscle, fat, cartilage or

pseudoangiomatous stromal hyperplasia (PASH) • Often categorised as B1 due to appearance of normal

tissue on core biopsy – clinical and radiological correlation is essential to avoid over treatment.

Breast Hamartoma - Variants

• Adenolipoma

• Fibrolipoma

• Adenofibroma

• Chrondrolipoma

• Myoid hamartoma

Case 2 (16/29962)


• Indeterminate 12mm focus, 6 o'clock right breast

• P1/U3

• Right breast core biopsy

Case 2. Diagnosis

Complex sclerosing lesion and usual epithelial hyperplasia

Radial Scar/Complex Sclerosing lesion

• Radial Scar • 10mm or less in diamter

• ‘central fibro-elastic zone from which radiate out tubular structures that are two layered and exhibit intraluminal proliferation’

• Immuno panel of myoepithelial markers can be useful to exclude tubular carcinoma or low grade ductal carcinoma

• Complex sclerosing lesion • More than 10mm in diameter

• Exhibit all the features of radial scar

• May be associated with superimposed apocrine metaplasia, papilloma formation and sclerosing adenosis

Radial Scar/Complex Sclerosing lesion

• Diagnostic core biopsy • Radial scars/CSL should be categorised as B3

• Radial scars/CSL can be associated with epithelial atypia and/or invasive carcinoma in a significant number of cases

• Presence of epithelial atypia within the lesion is important to record as the chance of malignancy in the subsequent excision is much higher

• Vacuum excision biopsy • Recommended technique for full assessment

• If EXCISIONAL VAB has fully assessed lesion and there is no epithelial atypia, it is reasonable to record the RS/CSL as B2 rather than B3

• Upgrading rate for atypia is around 12% and for invasive carcinoma is <2%

RS/CSL Radiology

• Spiculate lesions which can be misinterpreted as malignant

• Several characteristic features but none are specific and all can be seen in invasive carcinoma

Case 3 (16/29104)


• Indeterminate mass in right breast

• Excised following core biopsy

• Macro: 50mm in maximum dimension, lobulated firm white lesion

stromal hypercellularlity and atypia

Frequent mitoses

Case 3. Diagnosis

Borderline phyllodes tumour

Phyllodes Tumour (PT)

• Uncommon fibroepithelial neoplasm with biphasic proliferation of both epithelial and stromal components.

• “Phyllodes” - Derived from the Greek word “phyllon” meaning leaf, and “eidos” meaning form.

Phyllodes Tumour (PT)

‘Fibroepithelial architecture shows exaggerated intracanalicular pattern with leaf-like frond protruding into cystically dilated spaces accompanied by stromal hypercellularity’

Histopathology 2016, 68, 5-21 Phyllodes tumours of the breast: a consensus review

Arch Pathol Lab Med. 2016;140:665-671 Phyllodes Tumor of the Breast

WHO 2012 Classification of PT

Histologic Features Benign Borderline Malignant

Stromal cellularity Mild Moderate Marked

Stromal atypia Mild Moderate Marked

Mitoses per 10 hpf (x 40)

<5 5 – 9 >10

Stromal Overgrowth *

Absent Absent or focal Present

Tumour Margin Well defined Well defined or focal infiltrative

Infiltrative

Malignant heterologous element

Absent Absent May be present

Proportion of all phyllodes tumours

60 – 75% 15 – 20 % 10 – 20%

* Stromal overgrowth defined as presence of stroma without epithelium in at least one low-power field (x4 objective or x10 in a core biopsy)

Stromal cellularity and atypia

• No objective criteria for assessment which confounds grading attempts

• Practical advice is to centre on the most cellular/atypical zones of lesion

Stromal cellularity

• Mild hypercellularity • Slight increase in stromal cells compared with normal

perilobular stroma ( some suggest twice cellularity of normal stroma)

• Evenly spaced nuclei; no touching or overlapping

• Marked hypercellularity • Confluent areas of densely overlapping nuclei

• Moderate hypercellularity • Intermediate findings with some overlapping

Stromal atypia

• Mild atypia • Nuclei with little variantion in size; inconspicuous nucleoli

• Smooth nuclear contours

• Moderate atypia • Some variation in nuclear size

• Wrinkled nuclear membranes

• Marked atypia • Marked variation in nuclear size

• Coarse chromatin

• Irregular nuclear membranes with discernible nucleoli

Practical Application of WHO classification

• Guidelines ambiguous

• ‘A practical approach is to grade a phyllodes tumour as malignant when it shows ALL the histological changes of malignancy, and as borderline when not all the malignant characteristics are present’

Differential Diagnosis of malignant PT

• Metaplastic carcinoma • Malignant epithelial and stromal element

• Use a panel of cytokeratins and myoepithelial markers ( these can also be positive in some malignant PT)

• CD34 + ve favours PT but can also be + ve in metaplastic carcinoma

• Primary sarcoma of breast • Extremely rare

• Most sarcomas arising as a component of malignant PT

• Extensive sampling to exclude an epithelial component

• Clinical management is similar

PT practical management

• Benign phyllodes that have been enucleated without margins can be managed conservatively

• Borderline phyllodes should be completely excised but there is no agreement on ideal margin width

• Recurrent and malignant phyllodes tumours should be excised with clear margins

Case 4 (16/19862)


• Presented with left breast lump

• M4/U5

• Left breast excision at RD&E following biopsy in NDDH

• Macro: Irregular greyish lesion 22 x 15mm

ASMA

Desmin

β catenin

Immuno Profile

Positive Negative

Β catenin AE1/AE3

ASMA S100

Desmin CD34

Bcl2

Caldesmon

Case 4. Diagnosis

Mammary Fibromatosis

Mammary Fibromatosis

• Rare (< 0.2 % primary breast tumours)

• Typically women of reproductive age

• May arise within breast or chest wall fascia

• Benign and non-metastasising

• Infiltrative and locally recurrent if not completely excised

Fibromatosis – clinical features

• Usually solitary

• Non-tender

• Ill-defined mass

• May be spiculate on mammography mimiking malignancy

• Ultrasound and MRI more accurate at defining the lesion

• Can be associated with trauma and implants

• May arising in FAP, Gardener’s syndrome

Fibromatosis – Macro

Fibromatosis – Micro

• Irregular, non-encapsulated proliferation of spindle cells (fibroblasts and myofibroblasts)

• Formation of sweeping, interlacing fascicles

• Extension into surrounding parenchyma with entrapment of lobules and fat

• No epithelial component

• Evenly spaced nuclei with smooth membranes and delicate nucleoli

• Uniformaly distributed collagen (can be keloid –like)

• Small but conspicuous blood vessels

Fibromatosis – Immuno

Antibody Reactivity Staining pattern Coment

β catenin Positive Nuclear Correlates with β catenin and APC gene mutations

ASMA Positive Cytoplasmic Reflects myofibroblastic differentiation

Desmin Focally positive Cytoplasmic

CD34 Negative Excludes phyllodes

Pan cytokeratins

Negative Excludes metaplastic carcinoma

S100 Negative Excludes melanoma

ER/PR/AR Negative

Fibromatosis – Genetics

• Mutations in β catenin gene (CTNNB1) associated with nuclear staining in >80% of cases

• Nuclear expression of β catenin also seen in • 23% of metaplastic breast carcinoma • 94% of benign phyllodes tumour • 57% of malignant phyllodes tumour

• Mutations in exon 3 of CTNNB1 more frequent in breast fibromatosis

• * CTNNB1 mutations not present in MBC or PT • Association with FAP and germline mutations in

APC gene which regulates β catenin.

Fibromatosis - Differentials

• Low grade, fibromatosis-like, metaplastic breast carcinoma

– Express cytokeratins

– Minority of cases can also show some nuclear expression of beta catenin

• Myofibroblastoma

• Stromal component of phyllodes tumour

• Nodular fasciitis

• Solitary fibrous tumour

• Scar

Case 5 (14/26001)


• Left breast carcinoma in 2010.

• ER positive, on tamoxifen

• Recurrent lesion left breast in region of previous surgery

• Left mastectomy

p63 p63

CK5/6 SMM

Case 5. Diagnosis

Encapsulated (encysted/intracystic) papillary

carcinoma

Encapsulated papillary carcinoma (EPC)

• Controversy as to whether this is an in-situ or invasive lesion

• Pure forms categorised as B5a on core biopsy and staged as Tis

• Biopsy report should clearly document the nature of the lesion so that it is not confused with conventional DCIS

• Goal is to avoid over treatment • Exception: high grade nuclear morphology and/or

triple negative phenotype should be classified as invasive (B5b)

EPC – Histological features

• Central and solitary

• Thick fibrous capsule

• Monotonous neoplastic cells arranged in solid and cribriform patterns

• Delicate fibrovascular cores

• Mostly low or intermediate nuclear grade

• Lack of myoepithelial cells around periphery of tumours and around fibrovascular cores

• Typically strongly ER positive , HER2 negative

EPC- invasive components

• Small number of EPC associated with invasion

• Invasion characterised by tumour cells extending beyond the fibrous capsule and inducing stromal reaction

• Invasive component can be papillary or IDC NST

• Staging should only follow the invasive component and not include the EPC component

EPC –Differentials

• Papillary DCIS – Maintains myoepithelial layer around periphery

• Solid papillary carcinoma – Predominantly solid growth pattern

– Often lacks peripheral fibrous capsule

– More often multinodular

– Frequent neuroendocrine and mucinous differentiation

– Indolent behaviour

– Staged as Tis

EPC – behaviour and management

• > 80% have indolent invasive pattern

• Lymphovascular invasion (3%)

• Nodal metastases (3%)

• Local recurrence (7%) – in those lacking conventional invasive components

• Should be managed as in-situ disease

• High grade and micropapillary patterns can be considered as invasive

Case 6 (13/30811)


• 18mm mass left breast

• P1/M3/U4

• Left breast WLE

ER strongly and diffusely positive

Case 6. Diagnosis

Mucinous carcinoma

Mucinous (colloid) carcinoma

• 0.5 – 3 % of all invasive breast carcinoma

• Rare in younger women (mean age 71)

• Nodal metastases rare

• 10 year survival for pure form is better than invasive carcinoma (NST)

Mucinous (colloid) carcinoma - Micro

• Clusters of small uniform cells floating in lakes of extracellular mucin

• Tumour nests may be solid, acinar, cribriform

• Typically ER positive and HER2 negative


• Type A: paucicellular/ no neuroendocrine diff

• Type B: hypercellular/ neuroendocrine differentiation in 10-15%

• Type AB: intermediate

Classification based on molecular studies but has no clinical significance











Invasive Carcinoma – tumour typing categories

Pure special type: 90% or more of tumour shows classical histological features

Invasive carcinoma, no special type (NST): < 50% special type morphology

Mixed carcinoma: special type areas >50% but < 90%

Case 7 (17/4440)


• Previous lesion excised from left breast 2015

• M3, U4 lesion at surgical site ?recurrence

• Left breast core biopsy

CK7 p63

SMM MIB1

Case 7. Diagnosis

Recurrent adenomyoepithelioma

(Low Grade malignant adenomyoepithelioma previously

excised in 2015)

Adenomyoepithelioma (AME)

• Rare breast tumour

• Biphasic, neoplastic proliferation of luminal and myoepithelial cells

• Most tumours have a benign clinical course but local recurrences, malignant transformations and distant metastases are reported

Benign AME – clinical features

• Occurs in adults at any age (mean age 59)

• Presents as solitary palpable nodule

• Can occur in any location but most common in periphery

• Mammogram: rounded or lobulated mass, dense, sometimes indistinct margins

Benign AME – Gross Features

• Size range: 3 – 70 mm (average 25mm)

• Round to lobulated with firm texture

• Pink-white to grey-tan cut surface

Benign AME – Histology

• Biphasic tumour composed of epithelial-lined tubules surrounded by myoepithelial cells

• Dual population highlighted using immunostains • Varying patterns described:

• Tubular - proliferation of tubules and hyperplastic myoepithelial cells

• Spindle cell – predominantly composed of spindled myoepithelial cells with a few tubules

• Lobular - solid nests of myoepithelial cells proliferating around comporessed tubules

• Catergorised as B3 on core biopsy • Complete excision with clear margins recommended to

prevent recurrence

Atypical AME – Histology

• Features of atypia are subjective and poorly defined

– Increase in mitotic figures

– Cytonuclear atypia in the proliferating myoepithelial cell population

– Infiltrative borders

• Uncertain metastatic behaviour

• Lymph node metastases have been seen subsequent to diagnosis of atypical AME

Malignant AME – Histology

• Locally invasive borders

• High mitotic rate

• High grade nuclear pleomorphism

• Lymphovascular invasion

• Epithelial or myoepithelial components of AME can give rise to invasive carcinoma

Case 8 (16/24107; 16/26640)


• Left sided breast pain and lumpiness

• Mammogram and ultrasound scan normal (M1/U1)

• Follow-up MRI scan detect MRI3 lesion

• Patient proceeded to core biopsy (16/24107)

p63

CK5/6

S100 CD10

SMM ER

Summary

• Tubular/glandular and focally cribriform proliferation

• Dual population of cells with some basal/myoepithelial expression although not confined to the periphery of the tubules

• Eosinophilic luminal secretions

• S100 and ER negative

Provisional Diagnosis

• Atypical microglandular adenosis

• B3

• Further vacuum biopsy recommended at MDT

• Vacuum biopsy (16/26640)

ABDPAS

p63 ASMA

Collagen IV CK7

ER PgR

CD117 MIB-1 very low

Summary of vacuum biopsy findings

• Infiltrative lesion composed of tubular and prominent cribriform areas

• Dual luminal and basal cell population highlighted by immuno

• ER, PgR, S100 and CD117 negative

• DD: Adenoid cystic carcinoma; collagenous spherulosis

• Slides of core and vacuum biopsy sent to Professor Sarah Pinder for an expert opinion

Expert Diagnosis

• In keeping with ADENOID CYSTIC CARCINOMA

• Immuno panel not entirely typical (CD117 negative and only scant luminal cells)

• Tissue sent for molecular genetic testing (interphase FISH analysis)

• MYB (6q23) gene rearrangement present consistent with adenoid cystic carcinoma

Case 8. Diagnosis

Adenoid cystic carcinoma (AdCC)

Adenoid cystic carcinoma (AdCC)

• Uncommon; <0.1% of all breast carcinomas

• A salivary gland-type breast carcinoma

• Better prognosis than salivary AdCC

• Age distribution similar to other invasive breast cancers

• Mean size is 30mm (range 7 – 120mm)

• Radiologically non-specific features; can be misdiagnosed as benign

AdCC - Histology

• Typical dual population of luminal and myoepithelial-basal cells

• 3 architectural patterns: • Tubular/trabecular

• Cribriform

• Solid basaloid

• True glandular spaces and pseudolumina

• Luminal spaces contain PAS +ve neutral mucin

• Nottingham histological grading applies

AdCC – Immunohistochemistry

Myoepithelial –basal cells Luminal cells Hormone receptors

CK5/6 CK7 Triple negative

CK17 CK8/18 ER and PgR positive in a small minority

P63 EMA HER2 typically negative

Actin CD117 (positive in 90%)

Calponin

S100

Collagen IV – highlights pseudolumina

AdCC - Differentials

• Cribriform/tubular carcinoma • Monomorphic population of neoplastic cells • Typically ER and PgR positive • Rarely express p63 or CD117

• Collagenous spherulosis • Collagenous spherules are irregular and mostly observed at the

periphery of lesions • No mucosubstance within lumina • Typically CD117 negative and Calponin/SMM positive

• DD of solid variant of AdCC includes: • Small cell carcinoma • Solid papillary carcinoma • Metaplastic carcinoma • Lymphoma

AdCC – Molecular pathology

• T (6;9)(q22-23; p23-24) chromosomal translocation which generates fusion transcripts of the oncogene MYB and the transcription factor NFIB

• Translocation present in 90% of AdCC

• Next generation sequencing shows breast AdCC have basal phenotype

• No association found with BRCA1 mutations

AdCC – Prognosis

• Excellent prognosis – 10 year survival rate 90-100%)

• Lymph node metastasis (10-15%)

• Distant mets typically affect visceral organs

• Solid pattern associated with more aggressive behaviour

Case 9 (14/16598)


• Bleeding and crusting of left nipple with area of redness

• Nipple biopsy

CK7

CK5/6

p63

S100

ER

Case 9. Diagnosis

Paget’s disease of nipple

Paget’s disease of Nipple

• First described by James Paget in 1874

• Present in 1-2% of breast cancers

• Almost all cases associated with HG DCIS +/- invasive ductal carcinoma

• Excludes direct invasion of the skin by an invasive carcinoma

• Clinical features: red, weaping, crusting

Paget’s histology

• Adenocarcinoma cells within epidermis

• Cells either singly dispersed or efface the entire epidermis

• Large nuclei; prominent nucleoli

• Abundant pale cytoplasm

• Shrinkage artefact may leave space around cells

• Upper dermal telangiectasia and chronic inflammation

Paget’s differentials

Normal nipple skin Mammary Paget’s Pagetoid Bowen’s Melanoma

Toker cells = clear cells that occur in the epidermis of nipple skin

Described above No maturation and individual cell keratinisation

Pigmentation; dermal invasion can be present

CK5/6 +ve; CK7, CAM5.2 can be +ve

EMA, CAM5.2, CEA, CK7 +ve; HER2 +ve in 80-90% S100 +ve in 20% Mucin may be present

CK5/6; p63 +ve in epidermal cells and Bowen’s

HMB45; Melan A most specific S100 can be positive in Paget’s

References

• Histopathology Vol 68(1); Jan 2016: Annual Review Issue: Breast Pathology

• RCPath: Guidelines for non-operative diagnostic procedures and reporting in breast cancer screening (June 2016)

• RCPath: Pathology reporting of breast disease in surgical excision specimens incorporating the dataset for histological reporting of breast cancer (June 2016)

• World J Clin Cases 2014 December 16; 2(12):732-742: Adenoid cystic carcinoma of the breast: recent advances

Documents

Breast Pathology Cases Regional Training Day April 2017Breast Pathology Cases Regional Training Day April 2017 Dr Claire Murray Consultant Histopathologist Royal Devon and Exeter Hospital