Keywords
tall cell carcinoma -
IDH2 mutation - TCCRP - reversed polarity - case report
Introduction
Tall cell carcinoma with reversed polarity (TCCRP) is a rare malignancy introduced
as a new subtype under epithelial tumors of the breast as per the fifth edition of
World Health Organization (WHO) classification of breast tumors, 2019.[1] TCCRP has been categorized under “rare and salivary gland–type tumors” due to its
hallmark histological characteristics and molecular alterations. Crucially, this distinction
helps differentiate it from other papillary breast lesions.[1] TCCRP was formerly described by a variety of other terminologies, which are now
discouraged, including solid papillary carcinoma with reversed polarity, breast tumor
resembling tall cell variant of papillary thyroid cancer, and solid papillary breast
carcinoma resembling tall cell variant of papillary thyroid cancer.[1]
[2]
[3]
These tumors show morphological similarity to the tall cell subtype of papillary thyroid
carcinomas (PTCs) but are negative for thyroid transcription factor-1 (TTF-1) and
thyroglobulin. Additionally, RET/BRAF mutations, which are typically associated with PTC, are absent in these tumors.[2]
[4]
[5]
Identifying and categorizing this tumor as a separate entity is important due to its
indolent nature. TCCRP has characteristic histologic, immunohistochemical, and molecular
features that help distinguish it from other papillary lesions of the breast, as well
as PTC. We document this case for its rarity, unique histopathological and immunohistochemical
features, and the fact that it has a better clinical course, and may be misdiagnosed
as its more aggressive counterpart.
Case Report
A 42-year-old woman presented with a complaint of a lump in the left breast for over
3 months at an outside institution. Following initial evaluation, a wide local excision
was performed, which was histologically reported as invasive ductal carcinoma (no
specific type). A modified radical mastectomy was then scheduled and completed in
1 month. The slides and tissue blocks were sent to our institute for a second opinion
and further evaluation.
Microscopy
Histopathological examination revealed a fairly circumscribed breast tumor composed
of tall cells arranged predominantly in solid nests ([Fig. 1A]). These nests were surrounded by dense fibrous stroma, with some of the nests containing
central, thin fibrovascular cores ([Fig. 1B]), and collections of foamy histiocytes ([Fig. 1C]). Cystic areas filled with acellular, homogenous, eosinophilic material were also
noted within the tumor ([Fig. 1D]). The individual cells were columnar with abundant eosinophilic cytoplasm, arranged
in a palisading manner perpendicular to the basement membrane. The tumor cells had
round-to-ovoid bland nuclei, which demonstrated reversal of polarity, being localized
at the apex. Mitosis was relatively rare.
Fig. 1 (A) Nests of tumor cells (H&E, ×100). (B) Tumor nests with central fibrovascular cores (H&E, ×400). (C) Cyst macrophages within eosinophilic material (H&E, ×400). (D) Cystic space containing acellular eosinophilic material, lined by columnar cells
with reversed nuclear polarity (H&E, ×400). H&E, hematoxylin and eosin.
Immunohistochemistry
By immunohistochemistry (IHC), the tumor cells were positive for androgen receptor
(AR) and epidermal growth factor receptor (EGFR), focally positive for estrogen receptor
(ER) and progesterone receptor (PR). The cells were negative for human epidermal growth
factor receptor 2 (HER2/neu) ([Fig. 2]). E-cadherin positivity was noted, which was localized along the lateral membranes
([Fig. 3]). The expression of p63 protein was negative in the tumor cells. Ki-67 labeling
index was 10% in the hot-spot areas, suggesting reduced proliferative activity.
Fig. 2 (A) Tumor (H&E, ×400). (B) Focal positivity for ER (IHC, ×400). (C) Weak positivity for PR (IHC, ×400). (D) HER2/neu negative (IHC, ×400). (E) Positive AR expression (IHC, ×400). (F) Ki-67 labeling index 10% (IHC, ×400). AR, androgen receptor; ER, estrogen receptor;
H&E, hematoxylin and eosin; IHC, immunohistochemistry; PR, progesterone receptor.
Fig. 3 Characteristic lateral membrane E-cadherin staining (IHC, ×400). IHC, immunohistochemistry.
With the above characteristic morphologic features and IHC staining pattern, a diagnosis
of TCCRP was rendered in accordance with the essential criteria as per WHO.
The patient received four cycles of adjuvant chemotherapy and has remained disease-free
during the last 1 year of follow-up.
Discussion
As described initially in a series of five cases by Eusebi et al in 2003 as a breast
lesion with morphologic features strongly resembling PTC, our understanding of this
infrequent subtype of mammary carcinoma has grown over the years. Eusebi et al utilized
IHC to rule out thyroid metastasis and prove the origin of the lesion from the breast
(the lesional cells were consistently negative for TTF-1 and thyroglobulin).[2]
TCCRP has been reported only in women to date, and is known to occur at a median age
of 64 years with an age range between 39 and 89 years.[1]
[6] In the case described earlier, the tumor measured 2.2 cm in the biggest dimension,
which falls within the reported size range of 0.6 to 5 cm.[1]
[7] TCCRP has an excellent prognosis and very low metastatic potential, with very few
cases in the literature showing nodal metastasis.[1]
[7]
[8]
[9]
TCCRP shows considerable variation in its morphology. The tumor is composed of infiltrative
neoplastic cells often arranged in solid nests, follicular, and papillary patterns,
interspersed with occasional thin fibrovascular cores. Varying proportions of a cribriform
pattern may be identified in the tumor. In their case series, Chiang et al highlighted
that TCCRP characteristically demonstrated double layering of the columnar cells with
apically located nuclei and correlated the absence of apical and basal membrane E-cadherin
expression as confirmatory of the reverse polarization.[10]
[11]
Aggregates of foamy macrophages may be seen within the tumor nests. A few tumors also
show cystic areas filled with colloid-like material. The individual cells are cuboidal
to columnar with eosinophilic cytoplasm and a round to oval nucleus situated at the
apex. The abundance of mitochondria contributes to cytoplasmic eosinophilia.[11] Other features include the presence of nuclear grooving or pseudo-nuclear inclusions.
The tumor nests are often surrounded by a dense fibrous stroma.[1]
[2]
[12] The case we have described displayed many of these features. In addition, some cases
of TCCRP may be atypical with polygonal tumor cells, with only a few of them showing
reversed polarity.[13]
Based on histomorphology, the differential diagnosis includes metastatic deposits
from PTC or papillary lesions native to the breast, such as papillary carcinoma. The
thyroid rarely metastasizes to the breast and around 5% of such metastatic lesions
may be deposits from PTC.[5] In such instances, a detailed history, diagnostic imaging, and an appropriate IHC
panel are effective in delineating the origin of the lesion. In our patient, a thorough
physical examination was done at the time of presentation, and due to the lack of
findings suggestive of a thyroid lesion, the need to do thyroid imaging and thyroid
profile testing was ruled out.
TCCRP has its own specific immunohistochemical expression pattern. The tumor cells
are triple negative or may show focal weak positivity for ER and PR, but consistently
lack overexpression of HER2/neu. Low-molecular-weight cytokeratin CK7 and high-molecular-weight
cytokeratin CK5/6 show positive expression, a pattern resembling intraductal papilloma
with usual ductal hyperplasia, which is also a differential diagnosis. However, intraductal
papillomas are surrounded by myoepithelial cells, which are highlighted by p63 or
calponin, whereas TCCRP shows loss of the myoepithelial layer around the tumor nests.
Calretinin expression is frequently observed.[11]
[14] AR may or may not be expressed. In doubtful cases, origin from the breast is verified
by the expression of mammaglobin, GCDFP-15, or GATA3. TCCRP is invariably negative
for markers that denote thyroid origin, including TTF-1 and thyroglobulin. Ki-67 labeling
index is often low (<10%).[7]
[12]
[14]
[15]
Chiang et al described a series of 13 cases in which 10 cases (77%) harbored a hotspot
somatic mutation at R172 (Arg residue 172) of the IDH2 gene. This mutation allows gain of function with subsequent blockade of cellular
differentiation via hypermethylation of epigenetic sequences. Additionally, Chiang
et al documented the presence of concurrent mutations in PI3K pathway-related genes
such as PIK3CA.[1]
[3]
[10]
[16] Breast carcinomas rarely have characteristic genotype–phenotype mutations. Some
breast malignancies associated with specific mutations include mucoepidermoid carcinoma
(CRTC3–MAML2), adenoid cystic carcinoma (MYB–NFIB), lobular carcinoma (CDH1), etc. TCCRP falls into this category with an associated IDH mutation.[17]
[18]
IDH mutations are often detected in glioma, chondrosarcoma, cholangiocarcinoma, and acute
myeloid leukemia. TCCRP is the only invasive mammary carcinoma with an associated
IDH2 mutation.[1]
[6]
[17] Identification of IDH2 mutations in this tumor opens the door to the possibility of targeted therapy.[10] TCCRP may also show the presence of TET2 mutations.[3]
[16] Additional mutations associated with TCCRP in published literature include PRUNE2 mutations with ATM, KIT, and MET alterations.[7]
[14]
[19]
This is the first case of TCCRP reported at our institute. Though the diagnosis was
rendered mainly based on histomorphology, the use of IHC as a supplementary tool lent
strength to it. A molecular test may prove useful due to the characteristic mutations
associated with TCCRP; however, this is not mandatory for diagnosis as per the essential
and desirable diagnostic criteria outlined by WHO.[1] It is essential to precisely identify and document newer morphological subtypes,
as these are gray areas and will contribute critical information to the existing data
on their behavior and response to therapy over time. Our case report is limited by
the lack of molecular profiling data as well as the paucity of references available,
given that TCCRP is a newly classified entity.
Conclusion
TCCRP is a lesion that requires a high index of suspicion for diagnosis. We document
this case of breast tumor with specific histopathological features to contribute to
the growing body of literature on TCCRP. Understanding their morphology, which strikingly
resembles the tall cell subtype of PTC, is key to a precise assessment. IHC workup
and molecular analysis may be employed as ancillary studies to assist in doubtful
situations to distinguish it from its morphological mimickers. The favorable prognosis
associated with this malignancy underscores the importance of its accurate identification.
