Tall Cell Carcinoma with Reverse Polarity of Breast: Report of a Case with Unique Morphologic and Molecular Features
Mohamed JASSIM1, Chennagiri S PREMALATA1, Geeta V Patil OKALY1, Chunduri SRINIVAS2
1Department of Pathology, Kidwai Memorial Institute of Oncology, Bengaluru, INDIA
2Department of Surgical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, INDIA
Keywords: Breast carcinoma, Tall cell carcinoma, Reverse polarity, Solid papillary, IDH2
Breast carcinomas are a heterogeneous group of malignancy, having variable clinical outcomes depending on their cellular and molecular
properties. Tall cell carcinoma with reverse polarity (TCCRP) is a recently described rare entity, which shares morphological features with
tall cell variant of papillary thyroid carcinoma but has a distinct morphological, immunohistochemical, and molecular profile. We describe a
case of a 40-year-old female patient, who presented with lump in the breast. The patient underwent lumpectomy and was diagnosed as tall cell
carcinoma with reverse polarity. Immunohistochemistry and bi-directional Sanger sequencing for IDH2 mutation were used for diagnosis. Tall
cell carcinoma with reverse polarity is a rare and newly described entity with characteristic morphological and molecular findings, which carries
an excellent prognosis.
Tall cell carcinoma with reverse polarity (TCCRP) is a
rare type of invasive breast carcinoma with characteristic
immuno-morphologic and molecular findings and is
often difficult to diagnose. Eusebi et al., in 2003, reported
a rare variety of breast carcinoma having features similar
to papillary thyroid carcinoma described as “Breast
tumor resembling the tall cell variant of papillary thyroid
carcinoma” (1). These tumors were also called breast
tumor resembling the tall cell variant of papillary thyroid
carcinoma; solid papillary breast carcinoma resembling tall
cell variant of papillary thyroid carcinoma; solid papillary
carcinoma with reverse polarity (1–5). These tumors were
consistently immuno-negative for TTF-1, thyroglobulin
and HBME1, and there was no associated thyroid
malignancy. Chiang et al. described 13 more cases and also
identified the IDH2 hotspot mutations at R172 in these
tumors, which has become a defining feature of this entity
(4). We are presenting a case report of this rare entity in a
40-year-old female, currently named “Tall cell carcinoma
with reverse polarity” by the World Health Organization
(6) and there are only scattered case reports and very few
case series published in the world literature to the best of
A 40-year-old female presented with pain and a palpable
lump in the right breast for the past one month. Past history
and family history were not significant. Mammography
revealed a BIRADS IV lesion in the upper outer
quadrant. Fine needle aspiration cytology was reported as
proliferative breast disease with atypia, and trucut biopsy
was inconclusive for malignancy. Hence patient underwent
lumpectomy, which was followed later by modified radical
mastectomy with axillary clearance. The nodular lesion
excised was relatively circumscribed, grey-white to yellow
in color, firm in consistency, and measuring 5.5x4.5x4cm.
The resection margin was formed by the lesion. Grossly, no
areas of necrosis/hemorrhage were identified. Microscopy
showed a tumor composed of nodules of neoplastic cells
arranged in nests and solid papillary patterns with thin
fibrovascular cores. Papillae were lined by tall columnar
epithelial cells, having a moderate amount of granular
eosinophilic cytoplasm, oval nuclei with moderate nuclear
pleomorphism, nuclear overlapping, crowding, nuclear
grooves, optical clearing of chromatin, and occasional
intranuclear pseudo-inclusions. The linear arrangement
of nuclei situated away from the basement membrane, socalled
reverse polarity, was also seen at places. Foci with
fibrovascular cores having clusters of foamy macrophages and follicular structures with colloid-like eosinophilic
secretion were also noted. Mitosis was sparse (1-2 per 10
high power field). No necrosis, lymphovascular emboli, or
perineural invasion were noted (Figure 1A-F
Click Here to Zoom
|Figure 1: Histomorphological
features of Tall
cell carcinoma with reverse
A) Tumor composed of
compact solid nests in a
background of fibrotic
stroma, (H&E; x40).
B) Nest and papillae are lined
by tall columnar epithelial
cells, nuclei exhibiting reverse
polarity (arrow) (H&E; x100).
C) Tumor cells have
cytoplasm, oval nuclei
with chromatin clearing,
and intranuclear pseudoinclusion
inclusion) (H&E; x100).
D) Nuclei exhibit crowding,
overlapping and nuclear
groove (Inset show nuclear
groove) (H&E; x400).
E) Follicular structures with
colloid-like secretions (H&E;
F) Fibrovascular core with
foamy macrophages (H&E
Immunohistochemistry was performed using an automated
stainer (Ventana Benchmark XT system®) with Ultra-
View Universal DAB detection. The antibodies used were
GATA3, GCDFP-15, estrogen receptor (ER), progesterone receptor (PgR), Androgen receptor (AR), HER2/neu,
synaptophysin, chromogranin A, Bcl2, EMA, CK 5/6,
p63, thyroid transcription factor 1 (TTF-1), inhibin, and
Ki67. Antibody details are shown in Table I. The neoplastic
cells were immuno-positive for GATA3, CK5/6, EMA and
calretinin with patchy and weak expression for ER and PgR.
AR showed heterogenous staining pattern with peripheral
accentuation in the tumor lobules (Figure 2A-I), which has not been described earlier in the literature. While neoplastic
cells were immuno-negative for HER2/neu, synaptophysin,
chromogranin, Bcl2, GCDFP-15, TTF1, and inhibin, the
Ki67 proliferation index was 5%. No staining for p63 was
seen around the lobules. Immunohistochemical features of
the tumors are illustrated in Figure 2.
Click Here to Zoom
|Figure 2: A) Neoplastic cells show weak and patchy expression for ER (IHC; x100) and B) PgR (IHC; x400). C) AR showed heterogenous
staining pattern with intense staining at the peripheral of the tumor (IHC; x100). D) Neoplastic cells are positive for CK5/6 (IHC; x40),
E) Calretinin (IHC; x40), F) GATA-3 (IHC; x40), G) with luminal expression of EMA (IHC; x400). H) Low Ki67 proliferation (IHC;
x100) and I) negative for TTF-1 (IHC; x40).
DNA was isolated from formalin-fixed paraffin-embedded
blocks and targeted sequencing for the commonly mutated
site of IDH1 (R132) and IDH2 (R172) was performed
through a bi-directional Sanger sequencing method on the
amplified template. The tumor tissue showed a mutation
in the IDH2 gene (DNA description: c.A514>G; Protein
description: p.Arg172Gly – R172G). DNA sequence chromatogram
for the IDH2 gene is shown in Figure 3. Based
on the characteristic immuno-morphology and molecular
findings, a diagnosis of tall cell carcinoma with reverse
polarity was made. Following lumpectomy, completion
mastectomy with axillary lymph node dissection was performed
owing to the positive surgical margin. Grossly and
microscopically, no residual tumor was identified and all
nine axillary lymph nodes were free of tumor. PET-CT scan
revealed no evidence of metastasis. No further treatment
was given owing to the indolent behavior of the tumor, and
the patient is under observation and is currently diseasefree
for 6 months post-surgery. Written informed consent
for publication was taken from the patient.
Click Here to Zoom
|Figure 3: DNA sequence chromatogram showing mutation in IDH2 gene at R172.
Tall cell carcinoma with reverse polarity is a recently
described invasive breast carcinoma, included in the 5th
edition of WHO classification of breast tumors as a slowgrowing
tumor with favorable prognosis (1-6). These
tumors most commonly occur in women around the
age of 65 years (range 52 to 75years), with characteristic
immuno-morphologic features. Molecular studies have
shown IDH2 mutation in almost all of these tumors,
which has become a defining feature. Morphologically,
they form well-circumscribed masses with cells arranged
in compact solid nests in a background of fibrotic stroma,
having thin fibrovascular cores that recapitulates a solidpapillary
pattern, and sometimes the cores contain foamy
macrophages. Papillae are lined by tall columnar cells
having abundant eosinophilic cytoplasm, bland oval to
round nuclei exhibiting nuclear grooves and intranuclear
cytoplasmic inclusions (1,3). The most characteristic
feature is apical location of the nuclei resulting in reverse
polarity. Other features include low mitotic count and
absent myoepithelial cells at the periphery and within the
papillary fronds. Psammoma bodies, granular calcification,
and follicular structures with eosinophilic/amphophilic
colloid-like secretions are sometimes noted (7). Areas of
necrosis, lymphovascular emboli, or peri-neural invasions
are usually not seen (8). The present case showed all the above characteristic morphological features. These tumors
show weak or absent ER, PgR, AR expression, and are almost
always negative for HER2/neu. Although morphological
features of TCCRP resemble papillary thyroid carcinoma,
they are negative for TTF-1, thyroglobulin and HBME 1 (9,
10), and the breast origin of the neoplasm is confirmed by the
positive staining for markers of mammary differentiation
like GATA3, mammaglobin and GCDFP-15 (7,8,10,11).
Myoepithelial markers p63, SMMHC, and calponin are
absent within and around the lesion, suggestive of invasive
disease. Neoplastic cells are also immuno-positive for
CK5/6, and focally for EMA, CEA, and bcl-2, and exhibit
a low Ki67 proliferation index ranging from 1 to 5%
(3,5,8). All TCCRP also show diffuse and strong expression
calretinin. The immunohistochemical profile in the present
case was similar to the cases described in the literature,
with strong expression of GATA3, CK5/6, calretinin, and
weak expression of hormone receptors, and AR showed a
heterogenous staining pattern with peripheral accentuation
in the tumor lobules (Figure 2C), which has not been
described earlier in the literature. Ki67 proliferation was
low (5%). In addition, the neoplastic cells showed patchy
expression of GCDFP15 and luminal expression of EMA
(12). Chiang et al. performed molecular analysis on 13 cases
of TCCRP using whole-exome and targeted sequencing
and found that 77% of cases harbored IDH2 mutation at
R172 (4). Alsadoun et al., after genetic and transcriptomic
profiling of this tumor using whole-exome analysis, showed
that the IDH2 gene harbors a hotspot mutation at the
level of arginine 172 (R172), which was not present in any
other breast carcinoma, in 78% of TCCRP (7). Although
IDH2 mutations are commonly identified in many
tumors such as secondary gliomas, myeloid malignancy,
cholangiocarcinoma, microsatellite stable colorectal
cancer, chondrosarcoma etc., they are infrequent among
breast tumors but are typically seen in TCCRP (7, 13-17).
Pareja et al. demonstrated that immunohistochemistry
using a monoclonal antibody against IDH2 R172S (Clone
- 11C8B1) is sensitive and specific for TCCRP harboring
the IDH2 R172 hotspot mutation (18). Genetic alterations
prevalent in papillary thyroid carcinoma like RET/PTC
rearrangements and BRAF mutations (18,19) are almost
always absent in TCCRP. Bi-directional Sanger sequencing
on the paraffin block showed IDH2 hotspot mutations
at R172 in the present case, which is a characteristic and
unique molecular finding of this tumor. TCCRP has an
indolent clinical behavior with favorable outcomes with
surgery being the mainstay of treatment (3,4,8,20). It has the
potential for recurrence in case of incomplete excision of the tumor; thus complete excision with adequate margin is the
optimal treatment for TCCRP (3). However, two instances
of metastasis have been reported in literature: Cameselle-
Teijeiro et al. reported one case with bone metastasis and
Foschini et al. reported one case with intramammary lymph
node metastasis (5,8).
TCCRP should be differentiated from other papillary
lesions of the breast like encapsulated or solid papillary
carcinoma and invasive micropapillary carcinoma as it
shares papillary architecture with lack of myoepithelial
cells. TCCRP can be differentiated from these entities by
the characteristic morphology of cells with reverse polarity
and immuno-positivity for CK5/6, calretinin and negative
or weak expression of hormonal receptors. Intraductal
papilloma with usual ductal hyperplasia shares nuclear
groove and pseudo-inclusion with TCCRP but can be
differentiated by the presence of myoepithelial cell layer in
papilloma and usual ductal hyperplasia, while TCCRP lacks
a layer of myoepithelial cells.
In conclusion, TCCRP is a rare and newly described entity
with characteristic morphological findings that can mimic
other papillary lesions of the breast. IDH2 hotspot mutation
is a distinctive and characteristic finding in TCCRP. A
high index of suspicion is necessary to avoid misdiagnosis
of TCCRP as other papillary breast lesions or metastasis
from the thyroid, and accurate diagnosis of this entity is
necessary as it carries an excellent prognosis.
CONFLICT of INTEREST
None of the authors have any competing interests.
We thank Dr Vani Santosh, Professor of Neuropathology,
Department of Neuropathology, NIMHANS, Bengaluru,
for carrying out molecular analysis for IDH2 mutation.
Concept: CSP, Design: CSP, Data collection or processing:
MJ, Analysis or Interpretation: CSP, GVPO, Literature
search: MJ, Writing: MJ, CS, Approval: MJ, CS.
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