RARE VARIANTS OF INVASIVE

BREAST CARCINOMA OF NO

SPECIAL TYPE (IBC-NST)

• The prior WHO (4

ed. 2012) classied several

tumors as separate entities (listed below). Breast

tumors with these “special morphological

patterns” now fall under the umbrella category

of IBC-NST and are no longer considered to be

the following clinically distinct subtypes:

oncocytic, lipid-rich, glycogen-rich, clear cell,

sebaceous, carcinomas with choriocarcinoma-

tous and pleomorphic patterns, melanocytic,

and carcinomas with osteoclast-like stromal

giant cells.

INVASIVE BREAST CARCINOMA

WITH MEDULLARY PATTERN

• Medullary carcinoma, atypical medullary

carcinoma, and carcinoma with medullary

features were listed as special subtypes of breast

carcinoma in the prior WHO. This diagnostic

category has poor interobserver reproducibility;

these tumors also show overlapping histologic

features with carcinomas that have basal-like

molecular proles and carcinomas with BRCA1

Issue 18 || May 2022

WHAT’S NEW IN BREAST

PATHOLOGY 2022:

WHO 5

EDITION AND

BIOMARKER UPDATES

Kristen Muller,

Julie M. Jorns,

and

Gary Tozbikian

Department of Pathology and Laboratory Medicine,

Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

Department of Pathology, Medical College of Wisconsin,

Milwaukee, WI, USA

Department of Pathology, The Ohio State University

Wexner Medical Center, Columbus, OH, USA

Corresponding Author: Kristen Muller, DO

Department of Pathology and Laboratory Medicine,

Dartmouth-Hitchcock Medical Center, Lebanon,

NH, USA

E-mail: kristen.e.muller@hitchcock.org

ORCID

Kristen Muller

https://orcid.org/0000-0003-3166-4523

Julie M. Jorns

https://orcid.org/0000-0002-7777-6670

Gary Tozbikian

https://orcid.org/0000-0002-5941-5652

Abstract

The 5th edition WHO Classication of Breast

Tumours (2019) has introduced changes to our

practices. Highlights are presented below, with a

focus on modications to morphological subtype

categorization. In addition, we summarize impor-

tant updates to ER and PR testing made in the

2020 ASCO/CAP guidelines, and briey discuss

PD-L1 and Ki-67 testing in breast cancer.

mutations.

• Tumor inltrating lymphocytes (TILs) may

explain the good prognosis of these cancers.

• Carcinomas with a basal-like or medullary

pattern (i.e., well-circumscribed, high-grade,

syncytial architecture, necrosis, prominent

TILs, Fig. 1) now represent one end of the

spectrum of TIL-rich IBC-NST; “IBC-NST

with medullary pattern” has been proposed to

replace “medullary carcinoma.”

NEUROENDOCRINE TUMORS

• True primary neuroendocrine (NE) neoplasms

of the breast are rare. They are classied as

well-differentiated NE tumors (carcinoid-like

and atypical carcinoid-like) and poorly

differentiated NE carcinomas (small cell

neuroendocrine carcinoma and large cell

neuroendocrine carcinoma).

• Distinct NE features and expression of NE

markers by IHC are needed for diagnosis, since

varying degrees of NE differentiation may be

seen in IBC-NST, mucinous carcinomas, solid

papillary carcinomas, and others.

• Metastasis must be ruled out before considering

a primary breast NE tumor.

• Routine staining on IBC-NST that lacks

characteristic NE morphological features is not

recommended, due to the lack of clinical

relevance.

WELL-DIFFERENTIATED

LIPOSARCOMA IN PHYLLODES

TUMOR

• Malignant heterologous elements are among

the diagnostic criteria for malignant phyllodes

tumor.

• Adipocytic differentiation in the stromal

component of phyllodes tumor, that is morpho-

logically indistinguishable from well-differenti-

PathologyOutlines.com

WHAT’S NEW

IN PATHOLOGY?

Sponsored by an unrestricted grant from Roche

Fig. 1. IBC-NST with medullary pattern. High-grade

tumor with a syncytial growth pattern and prominent

TILs.

ated liposarcoma of soft tissue, has been found

to lack the characteristic MDM2 and CDK4

amplications seen in well-differentiated

liposarcoma (Fig. 2).

• Based on recent molecular ndings and

evidence supporting low metastatic risk, the

single criterion of well-differentiated liposarco-

matous differentiation is no longer recom-

mended for establishing the diagnosis of

malignant phyllodes tumor.

MUCINOUS

CYSTADENOCARCINOMA

• This recently described, rare, invasive breast

cancer subtype is characterized by cystic spaces

lined by neoplastic columnar epithelium with

papillae and abundant intracellular and

extracellular mucin.

• The tumor border is rounded/encapsulated but

there is lack of myoepithelium throughout.

• Coexistent DCIS may be present and is helpful

in supporting a breast origin.

TALL CELL CARCINOMA WITH

REVERSE POLARITY (TCCRP)

• This recently described, rare, invasive breast

cancer subtype has characteristic features that

include solid nests of tumor, set in brous

stroma, that have delicate brovascular cores

lined by bland columnar epithelial cells (Fig. 3).

• Cells have abundant eosinophilic cytoplasm

with nuclei present at the apical poles (i.e.,

reverse polarity) that may have grooves and

inclusions.

• Despite low grade morphology, these tumors

are positive for CK 5/6 and are triple negative

for ER, PR, and HER2. IDH2 p.Arg172

hotspot mutations have been reported in 84%

of tumors studied.

PROGNOSTIC AND PREDICTIVE

BIOMARKERS UPDATE

• PD-L1 (clone 22C3)

- On July 26, 2021, the United States Food

and Drug Administration (FDA) approved

pembrolizumab for high-risk early-stage

triple-negative breast cancer (TNBC) in

combination with chemotherapy as neoadju-

vant treatment; subsequently it was approved

as a single agent adjuvant treatment.

- The FDA converted the accelerated approval

of pembrolizumab, in combination with

chemotherapy, for the treatment of locally

recurrent unresectable or metastatic TNBC

tumors that express PD-L1 (clone 22C3)

with a combined positive score (CPS) ≥ 10.

- CPS is the number of PD-L1 staining cells

(tumor cells, lymphocytes, macrophages)

divided by the total number of viable tumor

cells, multiplied by 100.

CPS = × 100

Number of PD-L1 staining

cells (tumor cells, lymphocytes,

macrophages)

Total number of

viable tumor cells

• PD-L1 (clone SP142)

- On August 27, 2021, Genentech withdrew

its accelerated indication for atezolizumab

plus nab-paclitaxel for the treatment of

PD-L1 (clone SP142) positive advanced/

metastatic TNBC.

• Ki-67 (clone MIB-1)

- On October 13, 2021, the FDA approved

abemaciclib plus endocrine therapy for

hormone receptor positive, HER2 negative,

node positive early breast cancer patients

with a Ki-67 index ≥ 20%, who are at high

risk for recurrence.

- The FDA approved companion diagnostic to

abemaciclib is Ki-67 using the MIB-1

PharmDX/Dako Omnis antibody clone.

• 2020 ASCO/CAP ER/PR Guideline Update

Highlights (Arch Pathol Lab Med 2020

May;144:545-563)

- ER low-positive new reporting recommenda-

tion: “The cancer in this sample has a low

level (1%–10%) of ER expression by IHC.

There are limited data on the overall benet

of endocrine therapies for patients with low

level (1%–10%) ER expression, but they cur-

rently suggest possible benet, so patients are

considered eligible for endocrine treatment.

There are data that suggest invasive cancers

with these results are heterogeneous in both

behavior and biology and often have gene

expression proles more similar to ER-nega-

tive cancers.”

- PR testing is optional in DCIS.

- There is a new recommendation for laborato-

ries to establish a specic protocol to ensure

the validity of ER low-positive (1–10%) or

negative (0 or < 1%) interpretations and

results.

Dr. Muller has been an author for

PathologyOutlines since 2020 and part of

the PathologyOutlines editorial board since

2021. She is currently an Assistant Professor

at Dartmouth-Hitchcock Medical Center

where she practices Breast and Gynecologic

Pathology.

Dr. Jorns has been an author for

PathologyOutlines since 2014 and part of

the PathologyOutlines editorial board since

2020. She is currently an Associate Professor

at the Medical College of Wisconsin where

she primarily practices Breast Pathology.

Dr. Tozbikian has been an author for

PathologyOutlines since 2018, part of the

PathologyOutlines editorial board since

2019, and Deputy Editor in Chief for Breast

Pathology since 2021. He is currently an

Associate Professor at The Ohio State

University Wexner Medical Center where he

practices Breast and Genitourinary Pathology.

Meet the Authors

Fig. 2. Phyllodes tumor with liposarcomatous differ-

entiation. Other features (stromal atypia, mitotic activ-

ity) in this tumor supported the designation as malig-

nant phyllodes tumor.

Fig. 3. Tall cell carcinoma with reverse polarity (TC-

CRP). The tumor is characterized by infiltration of

nests of tumor cells with fibrovascular cores and

bland columnar cells with apically-located nuclei and

abundant eosinophilic cytoplasm.