1
RARE VARIANTS OF INVASIVE
BREAST CARCINOMA OF NO
SPECIAL TYPE (IBC-NST)
The prior WHO (4
th
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
th
EDITION AND
BIOMARKER UPDATES
Kristen Muller,
1
Julie M. Jorns,
2
and
Gary Tozbikian
3
1
Department of Pathology and Laboratory Medicine,
Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
2
Department of Pathology, Medical College of Wisconsin,
Milwaukee, WI, USA
3
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.
2
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.