Tall Cell Carcinoma of the Breast With Reverse Polarity: Expanding the Molecular Spectrum With Mutation.

1
Introduction
Tall cell carcinoma with reverse polarity (TCCRP) is a rare variant of breast carcinoma, first described by Eusebi et al. in 2003 and has since been recognized as a distinct histopathological entity in WHO classification of breast tumors [1]. TCCRP shares several key histopathological similarities with the tall cell variant of papillary thyroid carcinoma (PTC); however, its distinct immunohistochemical (IHC) profile and molecular alterations confirm it as a primary breast neoplasm rather than a metastatic thyroid carcinoma [2]. Majorities of TCCRP harbor IDH2 R172 hotspot mutations, along with PIK3CA, PIK3R1, and TET2 mutations [3]. Additionally, PRUNE2 mutations with ATM, KIT, and MET alterations have also been studied in cases of TCCRP [4]. The management options include breast conservation surgery with sentinel lymph node biopsy (SLNB) as standard approaches while adjuvant therapies such as radiotherapy, chemotherapy, and hormonal therapy are selectively employed based on tumor biology and clinical risk factors [5].
Here, we present a case of a 72‐year‐old female with HR‐positive TCCRP harboring the rare IDH1 R132H mutation and its successful management, thereby expanding the known molecular spectrum of this rare breast carcinoma.

2
Case History and Examination
A 72‐year‐old nonsmoker, nonalcoholic female, without any comorbidities and family history of malignancy, presented to our clinic with a gradually enlarging lump in her left breast which she had noticed for the past 1 month. The swelling was associated with scanty, purulent, and foul‐smelling nipple discharge. However, there was no breast pain, nipple retraction, or systemic symptoms in the form of fever and weight loss.
On physical examination, a firm to hard, irregular and nontender lump measuring approximately 2 × 2 cm was palpated in the upper outer quadrant of the left breast. The lesion was not separate from the surrounding breast tissue. The overlying skin and nipple–areolar complex appeared normal with no nipple discharge at the time of examination. Examination of the right breast and bilateral axillae revealed no abnormalities. Furthermore, the rest of systemic examinations were unremarkable.

3
Methods (Differential Diagnosis, Investigations and Treatment)
Based on the initial impression of a breast malignancy, the patient was advised for triple assessment of the breast lump. Breast ultrasonography demonstrated an irregular, ill‐defined, hypoechoic lesion with peripheral vascularity at 1 o'clock position measuring 1.0 × 1.2 × 1.2 cm. The lesion was categorized as BI‐RADS 4C. Similarly, mammographic assessment of the breasts revealed a disorganized glandular structure with features suspicious for malignancy, consistent with a BI‐RADS category 4 lesion (Figure 1). Additionally, a contrast enhanced computed tomography (CECT) of chest and abdomen was performed to assess locoregional as well as distant spread of the tumor. It demonstrated a heterogeneously enhancing, irregular, lobulated lesion in the upper outer quadrant of the left breast (22.1 × 19.4 × 21.2 mm) with central necrotic areas, confined to the fibroglandular layer without involvement of the pectoralis muscle, skin or axillary nodes. These findings were suggestive of carcinoma of the left breast with benign ipsilateral axillary lymphadenopathy (Figure 2).
Given the strong suspicion of breast malignancy on the initial radiographic evaluation, an ultrasound guided core biopsy of the lesion was planned. The histological examination revealed Grade 1 ductal invasive carcinoma of no special subtype without any lymphovascular invasion. Initial IHC analysis labeled the tumor as low proliferative (Ki‐67 proliferation index—8%), hormone receptor (HR) positive phenotype (estrogen receptor [ER] positivity of 88% and progesterone receptor [PR] positivity of 66%).
In view of localized disease, the patient underwent a left simple mastectomy with SLNB. Intraoperatively, a 2 × 3 cm firm lump was noted in the upper outer quadrant of the left breast. Postoperatively, on serial sectioning of the mastectomy specimen, the tumor measured 6.5 cm in greatest dimension, reflecting a multinodular growth pattern and larger infiltrative component not fully appreciated on imaging. Histopathological examination also revealed multiple, well‐circumscribed solid nodules composed of epithelial cells arranged in tubuloglandular and papillary patterns, with abundant eosinophilic cytoplasm and characteristic reverse nuclear polarity, showing predominantly bland nuclei with focal mild atypia (nuclear grooving, clearing, pseudoinclusions), rare mitoses, foamy histiocyte aggregates, and occasional intraluminal eosinophilic secretions—features consistent with TCCRP of the breast (Figure 3). Additionally, all six sentinel lymph nodes were negative for metastasis. The tumor was classified as histologic Grade 1 with a Nottingham score of 5 (glandular/tubular differentiation 3, nuclear pleomorphism 1, mitotic count 1) and staged as pT3 pN0 according to the AJCC 8th edition.
To further characterize the lesion and guide subsequent management, extended IHC and molecular analysis were performed. Tumor cells were positive for GATA3, E‐cadherin, IDH1, and EMA, with strong ER (70%) and moderate PR (25%) nuclear expression, and negative for HER2/neu, thyroglobulin, and synaptophysin. The Ki‐67 proliferation index was low (10%) (Figure 4). CK5/6 and p63 exhibited mosaic expression with loss of peripheral myoepithelial cells, while calretinin showed rare weak positivity. Molecular analysis was performed on formalin‐fixed, paraffin‐embedded (FFPE) tumor tissue using a PCR‐based sequencing kit targeting hotspot mutations in IDH1 exon 4 and IDH2 exon 4. The assay detected an IDH1 R132H mutation, while IDH2 R172 remained wild type. The test is validated for FFPE tissue and interpreted in conjunction with histopathology. No additional gene panels were performed (Table 1). These findings supported the diagnosis of TCCRP harboring an IDH1 R132H mutation, a rare, low‐grade variant of invasive breast carcinoma with low proliferative potential and HR positivity.
Given the final pathological stage pT3N0, adjuvant chest wall radiotherapy was administered in accordance with standard breast cancer management guidelines. The patient received adjuvant radiation therapy to the chest wall (40 Gy in 15 fractions) in order to reduce locoregional recurrence, followed by 5 years of hormonal therapy with letrozole at a dose of 2.5 mg daily, due to the tumor's strong ER positivity and low proliferative index.

4
Results and Conclusions (Outcome and Follow‐Up)
At 18 months of follow‐up, the patient remained clinically well and asymptomatic. A postradiation CECT of neck and chest demonstrated no enhancing lesion in the left chest wall, subcentimetric bilateral axillary lymph nodes (left 8 × 6 mm, right 15 × 9 mm), and peripheral ground‐glass opacities with interlobular septal thickening in the anterior and apical regions of the left lung, consistent with radiation‐induced pulmonary fibrosis with traction bronchiectasis (Figure 5). She is advised to undergo chest physiotherapy for supportive management. The patient continues on hormonal therapy with letrozole and remains under routine oncologic surveillance.

5
Discussion
Hitherto, there are 92 reported cases of TCCRP including the present case, with the first description in 2003. The median age at diagnosis ranges from 40 to 85 years with clear female predominance [5]. However, Ben Makhlouf et al. described a 34‐year‐old female patient, suggesting that TCCRP can rarely occur in younger women, despite the higher incidence in older individuals [6].
The clinical presentation of TCCRP is generally indolent, with most patients presenting with a palpable breast lump or lesions discovered on routine screening mammography, without features of aggressive or metastatic disease [5]. Less commonly, patients may report mastodynia or have incidentally detected small breast nodules as described in individual case reports [6, 7]. In contrast, our patient presented with a breast mass accompanied by purulent nipple discharge, which is an unusual initial manifestation of TCCRP, highlighting the potential for atypical presentations in this rare breast carcinoma.
Initial investigation modalities typically include ultrasonography, mammography supplemented by cross‐sectional imaging in the form of computed tomography (CT) and magnetic resonance imaging, primarily to assess local tumor extent and potential distant spread. On mammography, TCCRP usually appears as a high‐density mass with spiculated and lobulated margins, corresponding to BI‐RADS category 4 lesion; whereas CECT findings typically reveal an irregular, heterogenous, lobulated lesion confined to breast parenchyma without evidence of local and distant invasion [8]. In line with the literature, our patient's mammography demonstrated a BI‐RADS 4 lesion while CECT of chest and abdomen showed a heterogenous, irregular and lobulated lesion confined to breast tissue with no locoregional or distant spread.
Histologically, TCCRP is characterized by tall columnar epithelial cells with reversed nuclear polarity, a hallmark feature, and exhibits papillary, solid, or follicular‐like architecture. Other key features include nuclear grooves, intranuclear pseudoinclusions, abundant eosinophilic cytoplasm, and low mitotic activity, distinguishing it from other invasive breast carcinoma subtypes. In contrast, the tall cell variant of PTC typically exhibits psammoma bodies along with giant cells with clear nuclei [5, 9]. TCCRP also lacks peripheral myoepithelial cells, distinguishing it from intraductal papilloma [10].
IHC profiling and molecular analysis are essential for accurate diagnosis and therapeutic management. IHC profile of TCCRP reveals a distinctive pattern. Most cases exhibit triple‐negative or low HR expression, although few cases show weak hormonal positivity. Breast‐specific markers, including CK7, GATA3, E‐cadherin, EMA, and GCDFP‐15, are consistently positive, confirming breast origin, while TTF1 and thyroglobulin are negative, differentiating TCCRP from PTC. The Ki‐67 proliferation index is typically low (mean 4%–6%), reflecting the tumor's indolent nature [2, 5, 11]. In our case, IHC revealed GATA3, E‐cadherin, IDH1 and EMA with low Ki‐67 index of 10%, confirming the breast origin of the tumor and its low proliferative potential. Metastatic PTC was considered in the differential diagnosis given the morphologic resemblance. However, the tumor showed thyroglobulin negativity and strong GATA3 positivity, favoring a primary breast neoplasm. Clinical and radiologic evaluation revealed no thyroid lesion. Although PAX8 and TTF‐1 immunostaining were not performed, the combined morphologic, immunophenotypic, and molecular findings supported the diagnosis of TCCRP. Furthermore, solid papillary carcinoma of breast (SPC) was ruled out given the absence of classical histological features such as plasmacytoid cells, basal nuclei, and neuroendocrine features. This was further supported by synaptophysin negativity on IHC. Additionally, unlike most reported cases, our tumor exhibited strong ER (70%) and moderate PR (25%) expression, adding to the limited literature of HR‐positive TCCRP and supporting hormonal therapy with a favorable prognostic implication.
Molecular genetic testing frequently exhibits two characteristic comutations—IDH2 R172 and PIK3CA implicated in the pathogenesis and diagnosis of TCCRP [5, 6, 12]. Less commonly, mutations in PIK3R1, RTEL1 E839K, PRUNE2, ATM, TET2, KIT and MET genes are also associated with TCCRP [10, 12]. Although relatively specific for TCCRP, IDH1/IDH2 mutations can also appear in other malignancies, including gliomas, leukemias, and sinonasal undifferentiated carcinomas, underscoring the importance of correlation with histology and IHC [7, 13]. In our case, molecular analysis identified an IDH1 R132H mutation with wild‐type IDH2, representing a rare variant and expanding the known mutational spectrum of TCCRP. Furthermore, the absence of BRAF, MAPK or RET/PTC alterations typical of PTC supports the diagnosis of TCCRP [2, 14].
The management of TCCRP usually involves surgical intervention with or without adjuvant therapies. Treatment decisions are individualized based on tumor size, clinical stage, and patient preference. Breast conserving surgery (BCS) remains the most commonly performed procedure, particularly for small, localized tumors with low lymph node involvement [5]. In our case, a left simple mastectomy was performed due to the preoperative tumor size of 2.2 × 1.9 × 2.1 cm and the patient's preference, along with SLNB to assess the nodal status. Chemotherapy is typically reserved for patients with larger tumors (> 2 cm), nodal involvement, or aggressive histology (Ki‐67 index of more than 10%), while radiotherapy is administered to reduce locoregional recurrence. Hormonal therapy is generally considered in ER‐positive cases [5]. Our patient received adjuvant radiotherapy (40 Gy in 15 fractions) to prevent locoregional recurrence, followed by hormonal therapy with letrozole at a dose of 2.5 mg once daily due to the tumor's strong ER positivity (70%). The hormonal therapy has been planned for 5 years. As the tumor demonstrated ER positivity, the patient was initiated on adjuvant endocrine therapy with an aromatase inhibitor (letrozole), which represents a standard therapeutic approach for postmenopausal patients with ER‐positive breast carcinoma. Aromatase inhibitors such as letrozole, anastrozole, or exemestane are widely recommended endocrine therapy options for HR‐positive breast cancer [15, 16]. Chemotherapy was deferred due to the absence of nodal involvement and the tumor's low proliferative index, reflecting the generally indolent course of TCCRP.
The low recurrence rate highlights the favorable prognosis of TCCRP [5]. Consistently, post‐treatment CECT of our patient on 18 months follow‐up demonstrated no evidence of recurrence or metastasis. These outcomes reinforce the classification of TCCRP as a low‐grade malignancy with limited metastatic potential, particularly when managed with timely and appropriate therapeutic intervention.

6
Conclusion
This case illustrates the distinctive histopathological, immunophenotypic, and molecular profile of TCCRP—a rare and recently characterized subtype of breast carcinoma. Accurate diagnosis is crucial, as its indolent course and strong HR positivity make it amenable to manage with surgical and hormonal therapy, leading to an excellent prognosis as well as better quality of life. Additionally, the authors would like to encourage researchers and clinicians to investigate targeted therapies against IDH1/IDH2 and PIK3CA mutations, which may expand therapeutic options for this rare and molecularly distinct subtype.

Author Contributions

Abhisek Jha: conceptualization, project administration, supervision, writing – review and editing. Shristi Gupta: writing – original draft. Asmita Rayamajhi: conceptualization, project administration, supervision. Sajan Yadav: writing – original draft. Kuldeep Timilsina: writing – original draft. Pragati Gurung: writing – original draft. Amit Kumar Sah: writing – original draft.

Funding
The authors have nothing to report.

Consent
Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

Conflicts of Interest
The authors declare no conflicts of interest.