Tall Cell Carcinoma with Reversed Polarity of the breast: Clinicopathological insights, molecular profile, and future therapeutic directions

Abstract

Tall Cell Carcinoma with Reversed Polarity (TCCRP) is a rare and distinct subtype of invasive breast carcinoma, first described in 2003. It is histologically characterized by tall columnar epithelial cells with reversed nuclear polarity and shares morphological features with papillary thyroid carcinoma (PTC). However, its unique molecular signature, including IDH2 and PIK3CA mutations, differentiates it from other breast cancer subtypes. A retrospective systematic study of 91 published cases of TCCRP was conducted, including two cases from our institution. Clinical, pathological, molecular, and treatment-related data were collected and analyzed. Descriptive statistics and Kaplan-Meier survival analysis were employed to evaluate disease-free survival (DFS) and overall survival (OS). Subgroup analyses explored associations between clinical features, molecular markers, and outcomes. The median age at diagnosis was 64 years, with a predominance of small tumors (mean size: 10.4 mm, T1 stage). Histologically, hallmark features included reversed nuclear polarity (100 %), nuclear grooves, and intranuclear pseudoinclusions. Immunohistochemical analysis confirmed a triple-negative profile (ER-/PR-/HER2-) in most cases, with consistent breast-specific marker expression (GATA3, CK7). Molecular testing revealed frequent IDH2 R172 (84.6 %) and PIK3CA (72.5 %) mutations. Surgical management, predominantly breast-conserving surgery (BCS), was the primary treatment, with adjuvant therapies rarely utilized. At a median follow-up of 35.8 months, recurrence occurred in only 2.2 % of cases, and the overall survival rate was 100 %. TCCRP is a rare, low-grade breast cancer subtype with a favorable prognosis and low recurrence risk based on currently available data, but longer follow-up studies are needed to confirm this observation. Its distinct histological and molecular features enable accurate diagnosis and differentiation from other breast cancers and metastatic thyroid carcinoma. Given its indolent nature, conservative treatment strategies, including BCS, are effective, and adjuvant therapies can be minimized. Future research should explore targeted therapies for IDH2 and PIK3CA mutations to expand treatment options for this unique subtype.

Highlights

• •Tall Cell Carcinoma with Reversed Polarity (TCCRP) is a rare, distinct breast cancer subtype characterized by reversed nuclear polarity, low proliferative activity.
• •TCCRP exhibits favorable prognosis with a low recurrence rate (2.2 %) and excellent overall survival (100 %).
• •Molecular profiling identifies potential therapeutic targets, including IDH2 and PIK3CA mutations, highlighting opportunities for future research on targeted therapies.

1. Introduction

Tall Cell Carcinoma with Reversed Polarity (TCCRP) is a rare and distinct subtype of invasive breast carcinoma, first described in 2003 by Eusebi et al. [1]. under the term “breast tumor resembling the tall cell variant of papillary thyroid carcinoma”. Its name was initially derived from its histological resemblance to the tall cell variant of papillary thyroid carcinoma (PTC), marked by columnar cells with reversed nuclear polarity, prominent nuclear grooves, and intranuclear pseudoinclusions. Despite these morphological similarities, subsequent molecular and immunohistochemical studies confirmed its origin in the breast, leading the World Health Organization (WHO) in 2019 to classify it formally as TCCRP [2]. However, due to its low incidence and morphological overlap with other breast neoplasms, its recognition and accurate diagnosis remain challenging.

Histologically, TCCRP exhibits a distinct pattern characterized by tall columnar epithelial cells arranged in papillary, solid, or follicular-like structures. A hallmark feature is the reversed nuclear polarity, where nuclei are located away from the basement membrane [3,4]. This unique nuclear orientation, coupled with eosinophilic cytoplasm and prominent nucleoli, creates a striking morphological resemblance to PTC. However, unlike PTC, TCCRP consistently lacks thyroid-specific markers such as TTF-1 and thyroglobulin while expressing breast-specific markers like GATA3, CK7, and GCDFP-15 [[5], [6]]. The molecular profile of TCCRP further supports its classification as a unique breast cancer subtype, with frequent mutations in IDH2 (R172) and PIK3CA. These mutations are rarely observed in other types of breast carcinoma but are consistently present in TCCRP, highlighting its distinct genetic landscape and potential therapeutic implications [7].

The accurate diagnosis of TCCRP requires careful histopathological evaluation and immunohistochemical confirmation. Its morphological similarity to invasive papillary carcinoma, apocrine carcinoma, and even metastatic PTC can lead to diagnostic confusion [8]. While TCCRP typically exhibits a triple-negative breast cancer (TNBC) profile, its low proliferative index and indolent clinical behavior distinguish it from other aggressive TNBC subtypes [9]. Most reported cases are managed with breast-conserving surgery (BCS) and sentinel lymph node biopsy (SLNB), with adjuvant therapies often omitted due to the tumor's favorable prognosis. However, the lack of standardized treatment guidelines and large-scale clinical trials limits the establishment of evidence-based management strategies.

Given the limited number of reported cases and the evolving understanding of its pathological and clinical characteristics, this study aims to provide a comprehensive review of 91 published cases, including two cases treated at our institution. Through an in-depth analysis of clinical presentation, histological features, molecular profiles, treatment approaches, and patient outcomes, we seek to clarify the diagnostic criteria and therapeutic implications of TCCRP while exploring potential targeted treatment strategies based on its unique molecular signature. This study aims to bridge the current knowledge gap and provide a foundation for future research and clinical practice.

2. Materials and methods

2.1. Study design

This study is a retrospective systematic review of published literature on TCCRP from January 2003 to April 2024. We conducted a comprehensive search using the PubMed database to identify relevant case reports, case series, and retrospective analyses. To enhance the depth of analysis, two histopathologically confirmed cases of TCCRP treated at our institution were also included. Data from these cases, including clinical, pathological, treatment, and follow-up information, were extracted for detailed comparison and analysis.

2.1.1. Search strategy

A systematic search was conducted in the PubMed database to identify relevant studies on TCCRP. Predefined search terms were used to ensure comprehensive retrieval of case reports, case series, and histopathological reviews. The search terms included “Breast tumor resembling the tall cell variant of papillary thyroid carcinoma,” “Solid papillary carcinoma with reverse polarity,” “Tall cell carcinoma with reversed polarity,” and “Tall cell variant of papillary breast carcinoma.” Each search term was applied independently and in various combinations to broaden the search scope. Boolean operators such as "AND," "OR," and "NOT" were employed to refine the search results and exclude irrelevant articles. This approach maximized the yield of relevant literature while minimizing unrelated search results. Only peer-reviewed articles published between January 2003 and April 2024 were considered for inclusion.

2.1.2. Search criteria

The search was limited to articles published between January 2003 and April 2024. Only peer-reviewed case reports, case series, retrospective analyses, and histopathological reviews were considered eligible for inclusion. To ensure accessibility and data accuracy, only articles published in English or translated into English were included in the final analysis.

2.2. Inclusion and exclusion criteria

Studies were included if they met the following criteria: histopathologically and immunohistochemically confirmed diagnoses of TCCRP based on World Health Organization (WHO) criteria, including defining microscopic features such as reversed nuclear polarity, nuclear grooves, and specific molecular markers. Only cases with comprehensive clinical, pathological, and treatment data were considered, including surgical management details, histological findings, immunohistochemistry (IHC) results, and molecular profiles. To ensure robust survival analysis, cases with explicit follow-up and survival data were required, focusing on key endpoints such as disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS). Studies needed to report follow-up durations and survival outcomes clearly. Conversely, incomplete reports lacking essential clinical, pathological, or follow-up data were excluded. Abstract-only publications such as conference abstracts, posters, editorials, and non-peer-reviewed sources were also omitted due to limited data availability and lack of rigorous peer review. Additionally, duplicate cases reported across multiple publications were included only once, with preference given to the most comprehensive or recent publication. These criteria ensured the inclusion of only well-documented, peer-reviewed studies with complete and reliable data, maintaining high scientific rigor and minimizing data redundancy.

2.3. Data collection

2.3.1. Demographic data

Patient demographic data were extracted from the included studies, encompassing age, sex, and relevant family history of breast cancer. Tumor-related characteristics such as tumor size, laterality (left or right breast), clinical stage (T, N, M), and imaging findings, including BI-RADS scores, were documented when reported. These variables provided a comprehensive overview of the patient population and baseline clinical presentations.

2.3.2. Pathological data

Histological patterns of TCCRP were classified into papillary, solid, or follicular-like structures based on morphological appearance. Essential histological features such as reversed nuclear polarity, nuclear grooves, intranuclear pseudoinclusions, eosinophilic cytoplasm, and mitotic activity were recorded to ensure diagnostic consistency. Immunohistochemical (IHC) markers were carefully reviewed, including hormone receptors (ER, PR), human epidermal growth factor receptor 2(HER-2) and breast-specific markers (CK7, CK5/6, GATA3, GCDFP-15, mammaglobin, and E-cadherin). Thyroid-specific markers such as TTF-1 and thyroglobulin were also documented to exclude metastatic papillary thyroid carcinoma. The Ki-67 proliferation index was assessed as a measure of tumor cell proliferation. Molecular genetic mutations in IDH2 (R172 mutation) and PIK3CA were recorded when confirmed by next-generation sequencing (NGS) or polymerase chain reaction (PCR). Cases lacking molecular data were analyzed separately.

2.3.3. Treatment data

Treatment data included details of surgical procedures and adjuvant therapies. Primary surgical approaches were classified into BCS, mastectomy, SLNB, and axillary lymph node dissection (ALND). Adjuvant treatments such as chemotherapy (CT), radiotherapy (RT), and hormonal therapy (HT) were recorded when administered. If molecular-targeted therapies were used, the type of drug, duration of treatment, and clinical outcomes were also documented.

2.3.4. Prognostic data

Follow-up data were extracted to evaluate survival outcomes, including disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS). The follow-up period was calculated in months from the date of surgery. Recurrence data encompassed the time to recurrence, site of metastases (lymph nodes, bone, or visceral organs), and the number and location of metastatic lesions. These prognostic indicators provided a basis for survival and outcome analysis, facilitating an evaluation of clinical behavior and treatment efficacy in TCCRP cases.

2.4. Statistical analysis

2.4.1. Descriptive statistics

Data extracted from the included studies were analyzed using descriptive statistical methods to summarize clinical, pathological, treatment, and survival characteristics. Categorical variables such as estrogen receptor (ER), progesterone receptor (PR), HER-2 status, and the presence of molecular mutations (IDH2 and PIK3CA) were reported as frequencies and percentages. Continuous variables, including patient age, tumor size, follow-up duration, and Ki-67 proliferation index, were presented as mean, median, and range values. This approach facilitated a comprehensive summary of the key demographic, clinical, and molecular characteristics of patients with TCCRP.

2.4.2. Survival and prognostic analysis

Survival outcomes were evaluated based on disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS), measured in months from the date of primary surgery. Kaplan-Meier survival curves were constructed to estimate survival probabilities and visualize time-to-event data. Differences between survival curves were assessed using the log-rank test, with statistical significance set at a two-sided p-value of <0.05. This survival analysis method enabled a reliable comparison of patient outcomes across different clinical and molecular subgroups, offering valuable prognostic insights.

2.4.3. Subgroup analysis

To explore potential prognostic factors and treatment effects, subgroup analyses were performed based on key clinical and pathological variables. Clinical variables included tumor size (≤2 cm vs. >2 cm), type of surgical intervention (breast-conserving surgery [BCS] vs. mastectomy), and the receipt of adjuvant therapy (yes/no). Histological markers such as ER/PR/HER-2 status, Ki-67 proliferation index, and the presence of molecular mutations (IDH2 and PIK3CA) were also analyzed. Comparative evaluations were conducted to determine their potential associations with recurrence risk, treatment response, and survival outcomes. These subgroup analyses provided critical insights into prognostic factors and guided recommendations for individualized treatment strategies in patients with TCCRP.

3. Results

3.1. Demographics and tumor characteristics

Patient demographic and tumor characteristics were thoroughly analyzed to define the clinical profile of TCCRP. The median age at diagnosis was 64 years, with a range from 40 to 85 years, indicating a predominance among postmenopausal women. All patients were female, and no male cases were reported in the available literature. The mean tumor size was 10.4 mm, with a range of 6–55 mm, and 76.9 % (70/91) of the tumors measured ≤2 cm, classifying them as T1 stage. Regarding laterality, 38 cases (41.8 %) were located in the left breast, 35 cases (38.5 %) in the right breast, while the laterality was unspecified in 18 cases (19.8 %). Tumor staging data indicated that 76.9 % (70/91) were stage T1 (≤2 cm), and 23.1 % (21/91) were stage T2 (>2 cm). A family history of breast cancer was reported in 12 % (11/91) of cases, emphasizing the potential relevance of genetic predisposition in some patients. Research has shown that 15 % of TNBC cases are associated with BRCA mutation. Recently, studies have shown that mutated genes such as BARD1, BRCA1, BRCA2, PALB2, and RAD51D are also linked to an increased risk for TNBC. The summarized clinical characteristics, including age, tumor size, breast laterality, clinical staging, and family history of breast cancer, are presented in Table 1.

Table 1.

Clinical features of tall cell carcinoma with reversed polarity (TCCRP) of the breast reported in the literature.

References	Sex/Age	Site	Tumor size(cm)	Node status	Surgery	Adjuvant therapy	Follow-up(months)	Recurrences/Metastases
Eusebi et al., 2003	F/58	L-LIQ	1.2	UK	BCS	NAT	26	A&W
	F/70	R-UOQ	1.3	UK	Mastectomy	NAT	54	A&W
	F/57	L-UOQ	1.6	UK	BCS	NAT	28	A&W
	F/74	R	2	UK	BCS	NAT	108	A&W
	F/56	UK	0.8	UK	UK	UK	UK	UK
Cameselle-Teijeiro et al., 2006	F/64	R-LIQ	4.1	UK	Mastectomy + ALND	CT + RT + HT	32	Alive and bone metastasis
Tosi et al., 2007	F/80	R-LOQ	2.5/1.4	1/UK	BCS + SLNB	NAT	3	A&W
	F/45	R-UOQ	5	0/UK	BCS + SLNB	UK	5	A&W
	F/61	R	2	0/UK	BCS + SLNB	UK	8	A&W
	F/47	R	2.3	0/UK	BCS + SLNB	UK	10	A&W
Chang et al., 2007	F/66	L-UIQ	1.1	0/UK	BCS + SLNB	HT	12	A&W
Masood et al., 2012	F/57	L-U	3.7	0/14	Mastectomy + SLNB	UK	UK	UK
Colella et al., 2015	F/79	R	3	0/8	BCS + SLNB	NAT	18	A&W
Baohua Yu et al., 2015	F/53	R	1.8	UK	BCS	UK	UK	UK
Chiang et al., 2016	F/68	L	0.9	UK	UK	NAT	UK	UK
	F/62	L	0.8	0/2	BCS + SLNB	RT	77	A&W
	F/63	L	1.2	UK	UK	NAT	UK	UK
	F/79	R	UK	UK	UK	NAT	UK	UK
	F/64	R	1.8	0/2	BCS + SLNB	NAT	31	A&W
	F/51	R	0.8	0/3	BCS + SLNB	NAT	30	A&W
	F/64	L	1.4	0/1	BCS + SLNB	RT	29	A&W
	F/58	R	0.6	UK	UK	NAT	UK	UK
	F/66	R	0.9	0/3	BCS + SLNB	CT	20	A&W
	F/65	L	1.5	0/2	BCS + SLNB	CT + RT	37	A&W
	F/70	L	1.3	0/2	BCS + SLNB	NAT	12	A&W
	F/65	L	1.2	0/4	BCS + SLNB	NAT	UK	UK
	F/65	L	0.9	UK	UK	NAT	UK	UK
Foschini et al., 2017	F/58	L-LIQ	1.2	0/UK	BCS + SLNB	NAT	60 + 48	Alive and axillary lymph node metastases(1/10) + A&W
	F/80	R-LOQ	2.5	1/1	BCS + SLNB	NAT	120	A&W
	F/61	R	2	0/UK	BCS + SLNB	NAT	132	A&W
	F/62	L	1	ND	BCS	NAT	96	A&W
	F/51	L	2	ND	BCS	NAT	UK	UK
	F/58	L	0.8	0/UK	BCS + SLNB	NAT	24	A&W
	F/61	L	0.6	ND	BCS	NAT	124	A&W
	F/50	R	0.8	ND	BCS	CT + RT	84	A&W
	F/59	R-UOQ	2.5	ND	BCS	NAT	76	A&W
	F/48	L	2.2	ND	BCS	NAT	24	A&W
	F/85	R	1.5	ND	BCS	NAT	UK	UK
	F/64	L-LIQ	2	0/11	BCS + ALND	NAT	36	A&W
	F/77	R	1.2	ND	BCS	NAT	24	A&W
Bhargava et al., 2017	F/65	L	0.9	UK	BCS	UK	19	A&W
	F/77	L	1.7	UK	BCS	UK	recently	A&W
	F/48	R	1.2	UK	BCS	Neo-CT	19	A&W
Pitino A et al., 2017	F/65	R	0.7	0/UK	BCS + SLNB	NAT	34	A&W
Gai et al., 2018	F/55	R	UK	0/UK	Mastectomy + SLNB	UK	UK	UK
Alsodoun et al., 2018	F/63	L	1.6	ND	BCS	UK	UK	UK
	F/70	L	1.1	ND	BCS	UK	Lost	UK
	F/72	R	1	ND	BCS	UK	Lost	UK
	F/64	L	1.5	ND	BCS	UK	UK	UK
	F/71	L	0.9	ND	BCS	UK	UK	UK
	F/52	R	4	ND	BCS	UK	UK	UK
	F/69	L	1	0/UK	BCS + SLNB	UK	53	A&W
	F/57	R	1.2	ND	BCS	UK	UK	UK
	F/75	R	3	ND	BCS	UK	UK	UK
Lozada et al., 2018	F/60	UK	1.1	UK	UK	UK	UK	UK
	F/60	UK	2.1	ND	UK	UK	UK	UK
	F/67	UK	0.6	ND	UK	UK	UK	UK
Zhong, E. et al., 2019	F/70	L	1.3	UK	UK	UK	16-64(32)	A&W
	F/63	L	0.6
	F/63	R	1
	F/79	R	1.6
	F/69	L	1.2
	F/69	L	1.8 + 1.0
	F/71	R	1.7
	F/74	R	0.8
	F/76	L	0.7
Ding, L.M. et al., 2019	F/70	L	1.6	UK	Mastectomy	UK	9	A&W
Pareja, F. et al., 2020	F/85	UK	1.5	UK	UK	UK	UK	UK
	F/60	UK	2.1	0/UK	BCS + SLNB	RT	UK	A&W
	F/67	UK	1	UK	UK	UK	UK	UK
	F/59	UK	1.5	0/UK	BCS + SLNB	RT	UK	A&W
	F/48	UK	1.3	0/UK	BCS + SLNB	NAT	UK	A&W
	F/79	UK	1.6	0/UK	Mastectomy + SLNB	NAT	UK	A&W
	F/64	UK	1.2	0/UK	BCS + SLNB	RT	UK	A&W
	F/70	UK	1.3	UK	UK	UK	UK	UK
	F/67	UK	1.7	UK	UK	UK	UK	A&W
	F/62	UK	0.9	0/UK	BCS + SLNB	NAT	UK	UK
	F/60	UK	2.6	UK	UK	UK	UK	UK
	F/47	UK	1.3	UK	UK	UK	UK	UK
	F/80	UK	0.6	UK	UK	UK	UK	UK
	F/46	UK	0.6	UK	UK	UK	UK	UK
Haefliger, S. et al., 2020	F/60	R	0.8	0/UK	BCS + SLNB	NAT	8	A&W
Trihia, HJ. et al., 2021	F/71	R-UOQ	0.9	0/UK	BCS + SLNB	NAT	18	A&W
Zhang, X. et al., 2021	F/45	L	1.2	0/UK	BCS + SLNB	NAT	UK	UK
Cui L J et al., 2021	F/62	L	2	UK	Mastectomy	UK	UK	UK
Jassim, M. et al., 2021	F/40	R	5.5	UK	Mastectomy + ALND	UK	6	A&W
Wei, Y F. et al., 2021	F/72	R	2.2	0/UK	BCS + SLNB	NAT	6	A&W
	F/70	L	1.6	UK	BCS	UK	33	A&W
Lei Z.et al., 2024	F/65	L	2	UK	Mastectomy	NAT	48	A&W
Present study	F/59	L-LOQ	2.2	0/5	Mastectomy + SLNB	NAT	6	A&W
	F/69	L-UIQ	2.5	0/5	BCS + SLNB	NAT	13	A&W

Abbreviations: UK, unknown; LIQ, lower inner quadrant; LOQ, lower outer quadrant; UOQ, upper outer quadrant; UIQ, upper inner quadrant; NAT, no additional therapy; A&W, alive and well; SLNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection; RT, radiation therapy; CT, chemotherapy; Neo-CT, neoadjuvant chemotherapy; HT, hormone therapy; BCS, breast conserving surgery; ND, not done.

3.2. Pathological findings

3.2.1. Histological features

The histological features of TCCRP were consistent with classical descriptions, showing tall columnar epithelial cells with reversed nuclear polarity, a hallmark feature of the disease. The tumors displayed diverse architectural patterns, including papillary (40.7 %), solid (35.2 %), and follicular-like (24.1 %) growth patterns. Microscopically, characteristic findings included reversed nuclear polarity in 100 % of cases, nuclear grooves in 95.6 % (87/91), and intranuclear pseudoinclusions in 82.4 % (75/91). Eosinophilic cytoplasm was noted in 89.7 % (82/91), reflecting abundant cytoplasmic content. Mitotic figures were present in 12 % (11/91) of cases, with an average mitotic count of less than two per high-power field (HPF), suggesting a relatively low proliferative activity. These findings were essential for distinguishing TCCRP from other histological subtypes of invasive breast carcinoma.

3.2.2. Immunohistochemical (IHC) results

Immunohistochemical analysis provided crucial diagnostic confirmation. Hormone receptor testing showed ER expression in 27.3 % (24/88) of cases, while PR positivity was observed in only 10.7 % (8/75). HER-2 expression was negative in 100 % (49/49) of cases. Breast-specific markers such as GATA3 were positive in 89.7 % (80/89), CK7 in 100 % (91/91), CK5/6 in 78.4 % (69/88), and GCDFP-15 in 60.2 % (53/88), supporting a mammary origin. Thyroid-specific markers used to exclude metastatic thyroid carcinoma, such as TTF-1 and thyroglobulin, were negative in all cases (0/91). The Ki-67 proliferation index had a mean value of 4.6 % (range 1 %–20 %), indicating a low proliferative rate consistent with the indolent nature of the tumor. Detailed immunohistochemical profiles, including hormone receptor status, breast-specific markers, and thyroid-related markers, are summarized in Table 2.

Table 2.

Immunohistochemical profiles of tall cell carcinoma with reversed polarity (TCCRP) of the breast reported in the literature.

References	Sex/age	ER	PR	AR	HER-2	Ki-67(%)	CK7	GCDFP15	TTF1	GATA3	IDH2	PIK3CA
Eusebi et al., 2003	F/58	–	–	<1 %	UK	UK	+	+	–	UK	UK	UK
	F/70	–	–	–	UK	UK	+	–	–	UK
	F/57	–	–	–	UK	UK	+	–	–	UK
	F/74	–	–	–	UK	UK	+	–	–	UK
	F/56	UK	UK	UK	UK	UK	UK	UK	–	UK
Cameselle-Teijeiro et al., 2006	F/64	+	+	+	UK	UK	+	+	–	–	UK	UK
Tosi et al., 2007	F/80	–	–	–	UK	UK	+	+	–	UK	UK	UK
	F/45	+	+	–	UK	UK	+	+	–	UK
	F/61	+	–	UK	UK	UK	UK	–	–	UK
	F/47	+	+	–	UK	UK	–	–	–	UK
Chang et al., 2007	F/66	+	–	–	–	UK	+	+	–	UK	UK	UK
Masood et al., 2012	F/57	+	+	UK	–	UK	UK	UK	–	UK	UK	UK
Colella et al., 2015	F/79	–	–	UK	–	UK	UK	+	–	UK	UK	UK
Baohua Yu et al., 2015	F/53	+	–	+	–	20	UK	+	–	+	UK	UK
Chiang et al., 2016	F/68	–	–	UK	UK	UK	+	+	–	UK	10/13	7/13
	F/62	–	–	–	–	UK	+	–	–	UK
	F/63	<10 %	<10 %	–	UK	UK	+	+	UK	UK
	F/79	–	–	–	UK	UK	+	+	–	UK
	F/64	–	–	–	–	UK	+	+	–	UK
	F/51	<10 %	<10 %	–	–	UK	+	+	–	UK
	F/64	<10 %	–	–	–	UK	+	–	–	UK
	F/58	–	–	–	–	UK	+	–	–	UK
	F/66	–	–	–	–	UK	+	+	–	UK
	F/65	<10 %	–	UK	–	UK	–	–	–	UK
	F/70	<10 %	–	–	–	UK	+	+	–	UK
	F/65	–	–	–	–	UK	+	–	–	UK
	F/65	–	–	+	–	UK	UK	+	–	UK
Foschini et al., 2017	F/58	–	–	–	–	UK	+	UK	–	+	UK	UK
	F/80	–	–	–	–	UK	+	UK	–	+
	F/61	<1 %	–	–	–	UK	+	UK	–	–
	F/62	–	–	ND	–	UK	ND	UK	–	ND
	F/51	–	–	ND	–	UK	+	UK	–	ND
	F/58	<1 %	<1 %	–	–	UK	+	UK	–	ND
	F/61	–	–	–	–	UK	ND	UK	–	ND
	F/50	–	–	–	–	UK	+	UK	–	+
	F/59	–	–	–	–	UK	+	UK	–	–
	F/48	–	–	–	–	UK	+	UK	–	ND
	F/85	–	–	–	–	UK	+	UK	–	ND
	F/64	–	–	–	–	UK	ND	UK	–	+
	F/77	<1 %	<1 %	–	–	UK	+	UK	–	+
Bhargava et al., 2017	F/65	–	–	UK	UK	UK	UK	UK	UK	UK	–	+
	F/77	<1 %	<1 %	<1 %	–	5	UK	+	UK	+	+	–
	F/48	–	<1 %	60 %	UK	UK	UK	UK	UK	UK	+	+
Pitino A et al., 2017	F/65	<10 %	–	–	–	UK	+	+	–	UK	UK	UK
Gai et al., 2018	F/55	–	–	UK	UK	UK	+	–	–	+	UK	UK
Alsodoun et al., 2018	F/63	60 %	10 %	80 %	UK	2	+	+	–	UK	6/9	5/9
	F/70	–	–	15 %	UK	1	+	+	–	UK
	F/72	2 %	–	10 %	UK	1	+	+	–	UK
	F/64	–	–	–	UK	6	+	–	–	UK
	F/71	–	–	–	UK	1	+	+	–	UK
	F/52	20 %	20 %	<1 %	UK	1	+	+	–	UK
	F/69	–	–	–	UK	1	+	–	–	UK
	F/57	5 %	–	8 %	UK	2	+	+	–	UK
	F/75	<1 %	<1 %	–	UK	15	+	+	–	UK
Lozada et al., 2018	F/60	–	–	UK	–	UK	UK	UK	UK	UK	+	–
	F/60	–	–	UK	–	UK	UK	UK	UK	UK	+	+
	F/67	–	–	UK	–	UK	UK	UK	UK	UK	+	+
Zhong, E. et al., 2019	F/70	+	–	UK	–	UK	UK	UK	UK	UK	7/9	6/9
	F/63	–	–	UK	–	UK	UK	UK	UK	UK
	F/63	–	–	–	–	UK	UK	UK	–	UK
	F/79	UK	UK	UK	UK	UK	+	UK	–	UK
	F/69	+	–	UK	–	UK	UK	UK	UK	UK
	F/69	–	–	UK	–	UK	UK	+	–	+
	F/71	–	–	UK	–	UK	UK	–	–	+
	F/74	–	–	UK	UK	UK	UK	UK	UK	UK
	F/76	<1 %	<1 %	UK	UK	UK	UK	UK	UK	UK
Ding, L.M. et al., 2019	F/70	–	–	UK	–	2	UK	UK	–	UK	+	+
Pareja, F. et al., 2020	F/85	–	UK	UK	UK	UK	UK	UK	UK	UK	14/14	7/14
	F/60	–	UK	UK	UK	UK	UK	UK	UK	UK
	F/67	–	UK	7 %	UK	UK	UK	UK	UK	UK
	F/59	+	UK	5 %	UK	UK	UK	UK	UK	UK
	F/48	+	UK	2 %	UK	UK	UK	UK	UK	UK
	F/79	UK	UK	–	UK	UK	UK	UK	UK	UK
	F/64	+	UK	5 %	UK	UK	UK	UK	UK	UK
	F/70	–	UK	7 %	UK	UK	UK	UK	UK	UK
	F/67	–	UK	–	UK	UK	UK	UK	UK	UK
	F/62	–	UK	–	UK	UK	UK	UK	UK	UK
	F/60	+	UK	15 %	UK	UK	UK	UK	UK	UK
	F/47	–	UK	<1 %	UK	UK	UK	UK	UK	UK
	F/80	+	UK	20 %	UK	UK	UK	UK	UK	UK
	F/46	–	UK	UK	UK	UK	UK	UK	UK	UK
Haefliger, S. et al., 2020	F/60	–	–	–	–	UK	+	UK	–	+	+	+
Trihia, HJ. et al., 2021	F/71	–	–	–	–	UK	UK	–	–	+	UK	UK
Zhang, X. et al., 2021	F/45	–	–	+	–	5	UK	+	–	+	+	+
Cui L J et al., 2021	F/62	–	–	UK	–	UK	+	+	–	+	+	UK
Jassim, M. et al., 2021	F/40	<1 %	<1 %	–	–	5	UK	–	–	+	+	UK
Wei, Y F. et al., 2021	F/72	<1 %	–	UK	–	5	UK	+	+	+	+	+
	F/70	<1 %	–	UK	–	2	UK	+	–	–	+	+
Lei Z.et al., 2024	F/65	–	–	–	–	3	UK	UK	–	UK	+	+
Present study	F/59	<1 %	<1 %	UK	–	5	+	UK	UK	+	+	UK
	F/69	<1 %	–	5 %	–	5	UK	+	–	+	+	+

Abbreviations: ER, estrogen receptor; PR, progesterone receptor; AR, androgen receptor; HER-2, human epidermal growth factor receptor; CK, cytokeratin; E-cad, E-cadherin; TTF1, thyroid transcription factor-1; GCDFP15: Gross cystic disease fluid protein 15; GATA: GATA binding protein-3; UK, unknown.

3.2.3. Molecular mutations

Molecular genetic testing identified two key mutations: IDH2 R172 and PIK3CA, which were frequently co-mutated. The IDH2 R172 mutation was present in 85.2 % (52/61) of cases, representing a critical molecular hallmark of TCCRP. PIK3CA mutations were detected in 62.1 % (36/58) of cases, supporting the oncogenic relevance of the PI3K/AKT pathway in TCCRP pathogenesis. No cases exhibited BRAF V600E mutations or RET gene rearrangements, effectively ruling out metastatic thyroid carcinoma. These findings underscore the distinct molecular landscape of TCCRP, providing potential avenues for targeted therapy in future clinical trials.

3.3. Treatment and prognosis

3.3.1. Surgical treatment

Surgical treatment strategies were tailored based on tumor size, patient preference, and clinical staging. Among the reported cases, BCS was the most commonly performed procedure, accounting for 83.9 % (52/62) of cases, reflecting the generally small tumor sizes and low incidence of lymph node involvement. Simple mastectomy was performed in 16.1 % (10/62) of cases, typically due to patient preference or the presence of multifocal disease. SLNB was conducted in 67.4 % (41/61) of cases to assess lymph node status. ALND was performed in only 6.5 % (4/61) of cases, primarily reserved for patients with confirmed axillary metastases on preoperative imaging or positive SLNB results. Notably, the low rate of axillary involvement reinforced the indolent nature of TCCRP. The high proportion of patients undergoing BCS underscores the feasibility of breast-conserving surgery in TCCRP management, given its localized presentation and favorable clinical course.

3.3.2. Adjuvant therapy

Adjuvant therapy was administered based on individual tumor characteristics, receptor status, and clinical risk factors. Chemotherapy (CT) was utilized in 5.5 % (5/91) of cases, primarily reserved for patients with larger tumors (>2 cm), lymph node involvement, or histologically aggressive features such as increased Ki-67 expression (>10 %) or a higher mitotic index. Notably, the limited use of chemotherapy reflects the indolent nature of TCCRP, even when classified as a triple-negative breast cancer subtype.

Radiotherapy (RT) was delivered in 9.9 % (9/91) of cases, primarily after BCS to reduce the risk of locoregional recurrence. The relatively low rate of RT administration, despite the high proportion of patients undergoing BCS, underscores the favorable prognosis and limited recurrence risk associated with TCCRP. However, the absence of radiotherapy in a significant proportion of patients might also reflect individualized treatment decisions driven by patient comorbidities, age, or physician preferences based on perceived low tumor aggressiveness.

Hormonal therapy (HT) was administered in only 2.2 % (2/91) of cases, exclusively in patients with weakly positive estrogen receptor (ER) expression (<10 %), reflecting TCCRP's frequent triple-negative immunohistochemical profile. The limited use of HT highlights the rarity of hormone receptor expression in TCCRP and aligns with its typical receptor-negative biology.

Despite the identification of actionable genetic mutations such as IDH2 R172 and PIK3CA in a substantial proportion of cases, no patients received molecular-targeted therapies. This therapeutic omission is likely due to the absence of established clinical guidelines for TCCRP, a rare subtype without dedicated clinical trials. Given the high mutation rates in IDH2 (84.6 %) and PIK3CA (72.5 %), future research should explore the potential clinical utility of targeted therapies such as IDH2 inhibitors or PI3K/AKT/mTOR pathway inhibitors. Such agents could potentially expand the therapeutic landscape for TCCRP beyond conventional breast cancer treatment protocols.

3.3.3. Follow-up and recurrence

The median follow-up duration across the included cases was 35.8 months, with a range of 3–132 months. During this period, only two cases (2.2 %) experienced recurrence. One patient developed isolated bone metastases 32 months after surgery, while another experienced axillary lymph node recurrence 60 months postoperatively. Both cases were subsequently managed with additional surgical intervention, including ALND and radiotherapy. The low recurrence rate underscores the generally favorable prognosis associated with TCCRP. At the last follow-up, all patients with available survival data were alive, yielding an overall survival (OS) rate of 100 %. This excellent survival outcome further supports the classification of TCCRP as a low-grade malignancy with limited metastatic potential, particularly when treated with timely and appropriate surgical intervention. These findings suggest that patients with localized TCCRP tumors may benefit from a conservative treatment approach, minimizing the need for aggressive systemic therapies.

4. Clinical presentation

4.1. Case one

A 59-year-old female presented with a palpable lump in the lower outside quadrant of the left breast. Past history and family history were not significant. The mammary ultrasonography revealed a hypoechoic nodule of 2.1∗1.7∗1.8 cm in size at 5 o'clock, with an irregular shape, obscure boundary, nonuniform internal echo, blood flow signals at the periphery, and a score of five under the Breast Imaging Reporting and Database System (BI-RADS). The bilateral Mammography showed that a BI-RADS IV asymmetric high-density lesion in the left lower outer quadrant and no malignant calcification foci was detected. Magnetic resonance imaging revealed a BI-RADS V irregular mass, measuring 2.5∗2.1∗1.5 cm, and indicating the lesion was highly suspicious for malignancy (Fig. 1). The tumor cells were detected by Fine needle aspiration cytology. Hence, the patient underwent simple excision and sentinel lymph node biopsy (SLNB) as treatment.

Fig. 1.

(A: HE, low magnification; B: HE, 100 × magnification; C: HE, 200 × magnification) Histological appearances of tall cell carcinoma with reversed polarity. Tumor cell nuclei are arranged away from the basement membranes and towards the glandular lumina (reversed polarity).

(D: CK5/6×, 100 × magnification; E: CK7, 100 × magnification; F: GATA3, 100 × magnification) The cells were membrane positive for CK5/6、CK7 and GATA3.

Mammography(H): An irregular, high-density mass with spiculated and lobulated margins measuring approximately 2.1 × 1.9 cm was detected in the outer quadrant of the left breast. The lesion had poorly defined borders, and its appearance was classified as BI-RADS 4B.

Breast Ultrasound(I): A hypoechoic nodule with indistinct margins, irregular shape, and heterogeneous internal echogenicity was identified in the outer quadrant of the left breast, measuring approximately 2.1 × 1.7 × 1.8 cm. Penetrating strip-like blood flow signals were observed at the anterior margin. BI-RADS 5 classification was assigned.

Breast MRI(J): An irregular mass with spiculated margins was located in the posterior lower outer quadrant of the left breast, measuring approximately 2.5 × 2.1 × 1.5 cm. The lesion exhibited high signal intensity on T2WI and DWI sequences. After contrast administration, early enhancement with a washout-type TIC pattern was observed. The mass was classified as BI-RADS 5.

A:HE∗100; B:HE∗200; C:ER∗100; D:PR∗100; E:HER2∗100; F:Ki-67∗100.

Postoperative paraffin pathology confirmed the diagnosis of TCCRP with a maximum diameter of 2.2 cm and negative for sentinel lymph nodes (0/5). The immunohistochemical results (IHC) showed that negative expression of P63 and human epidermal growth factor receptor 2 (HER-2), weak expression for estrogen receptor (ER) and progesterone receptor (PgR) and positive expression of CK5/6, CK7, GATA3, CR and E-cad. The Ki-67 proliferative index was around 5 %. Immunohistochemical features of the tumors are illustrated in Table 2. Molecular genetic analysis was conducted using Next-generation sequencing (NGS), and the results showed concurrent IDH2 and PIK3CA hotspot mutations, thus confirming the diagnosis. No hormone therapy, adjuvant radiotherapy and chemotherapy were given owing to the indolent behavior of the tumor. The patient was alive and was currently disease free for 6 months post-surgery.

4.2. Case two

A 69-year-old female presented with a palpable lump in the upper inner quadrant of the left breast. She had a history of hypertension and diabetes, with no significant family history. Mammary ultrasonography revealed a hypoechoic nodule measuring 1.5 × 1.5 cm in the upper inner quadrant of the left breast, with an irregular shape, indistinct boundary, and abundant blood flow signals. The Breast Imaging Reporting and Database System (BI-RADS) score was 4C. Additionally, multiple hypoechoic nodules were observed in the left axilla, the largest measuring approximately 2.2 × 0.9 cm, with visible lymphatic hilum structure. Magnetic resonance imaging (MRI) revealed a solitary lesion in the upper inner quadrant of the left breast, measuring 1.6 × 1.6 × 1.2 cm. It appeared hypointense on T1-weighted imaging (T1WI) and hyperintense on fat-suppressed T2-weighted imaging (T2WI). The BI-RADS score was V (Fig. 2). Tumor cells were detected by fine needle aspiration cytology (FNA). Hence, the patient underwent breast-conserving surgery with sentinel lymph node biopsy (SLNB) for left breast cancer.

Fig. 2.

(A: HE, 100 × magnification; C: HE, 200 × magnification) Histological appearances of tall cell carcinoma with reversed polarity. Tumor cell nuclei are arranged away from the basement membranes and towards the glandular lumina (reversed polarity).

(C: ER, 100 × magnification; D: PR, 100 × magnification; E: HER2, 100 × magnification; F: Ki-67×, 100 × magnification) The cells were negative for ER, PR and HER-2. The number of Ki-67 positive cells was 5 %.

Breast Ultrasound(H): A hypoechoic nodule with unclear margins, irregular shape, and abundant blood flow signals was identified in the upper inner quadrant of the left breast, measuring approximately 1.5 × 1.5 cm. The lesion was classified as BI-RADS 4C.

Breast MRI(I): A solitary lesion measuring approximately 1.6 × 1.6 × 1.2 cm was located in the upper inner quadrant of the left breast. The lesion exhibited low signal intensity on T1WI, high signal intensity on T2WI with fat suppression, and high signal intensity on DWI. After contrast enhancement, heterogeneous internal enhancement with a washout-type TIC pattern was observed. The lesion was classified as BI-RADS 4.

Postoperative paraffin pathology confirmed the diagnosis of highly cellular carcinoma with polarity reversal (TCCRP), with a maximum diameter of 2.5 cm. No definitive evidence of neural invasion or vascular tumor emboli was found. Sentinel lymph nodes were negative for metastasis (0/5). The surgical margin was not negative. Immunohistochemical (IHC) results showed negative expression for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and CK5/6. GATA3 was strongly positive (3+), Calponin was negative, and GCDFP15 was positive. The Ki-67 proliferative index was 5 %. Molecular genetic analysis was performed using next-generation sequencing (NGS), revealing concurrent IDH2 and PIK3CA mutations, thus confirming the diagnosis. No adjuvant radiotherapy or chemotherapy was administered postoperatively. Thirteen months after surgery, the patient remained alive and disease-free.

5. Discussion

The present study highlights several critical findings that enhance the understanding of TCCRP as a unique and relatively indolent breast cancer subtype [10]. TCCRP demonstrated a notably favorable prognosis, with a recurrence rate of only 2.2 % and an overall survival (OS) rate of 100 % during a median follow-up of 35.8 months. This low recurrence rate, even in the absence of aggressive adjuvant therapy, suggests that TCCRP behaves less aggressively than other triple-negative breast cancers (TNBC), distinguishing itself as a low-risk malignancy. Histologically, TCCRP consistently exhibited hallmark features such as reversed nuclear polarity, nuclear grooves, and intranuclear pseudoinclusions, which were observed in all reported cases, supporting their role as reliable diagnostic criteria [11,12]. On a molecular level, IDH2 R172 and PIK3CA mutations were detected in over 80 % of the cases, underscoring the tumor's unique molecular signature [13]. The absence of typical TNBC-associated mutations, such as BRAF V600E and RET gene rearrangements, further reinforced the distinction between TCCRP and other aggressive breast cancer subtypes. Despite its TNBC classification, TCCRP displayed low aggressiveness, warranting a conservative treatment approach [14]. Chemotherapy was used in only 5.5 % of cases, primarily for larger tumors or lymph node-positive disease, while radiotherapy was administered in 9.9 % of cases, mostly after BCS. The limited need for adjuvant therapies despite a triple-negative immunophenotype highlights the importance of individualized treatment strategies tailored to the unique biological behavior of this rare subtype [15].

5.1. Clinical implications

The findings from this study have several important clinical implications that could inform future diagnostic, surgical, and therapeutic approaches for managing TCCRP. Despite its classification as a TNBC, TCCRP demonstrates distinct histological and molecular features that support a more conservative and personalized treatment strategy, reducing unnecessary treatment intensity while maintaining excellent clinical outcomes.

• 1)Early Molecular Screening for TNBC Patients with Suspicious Histological Features

Given the significant histological overlap between TCCRP and other breast cancer subtypes, especially low-grade TNBC and papillary carcinomas, early molecular screening should be considered in patients with ambiguous histological findings [16]. Key histological features that raise suspicion for TCCRP include reversed nuclear polarity, nuclear grooves, eosinophilic cytoplasm, and a low mitotic index. Standard histopathological evaluation should be complemented by next-generation sequencing (NGS) to detect defining molecular mutations such as IDH2 R172 and PIK3CA. Identifying these mutations could provide diagnostic certainty, avoid misclassification, and guide individualized management. Importantly, molecular screening could also uncover additional actionable targets, supporting precision oncology in challenging or unclear cases. Given the availability of cost-effective genetic panels, integrating NGS into routine pathological workflows for high-risk or triple-negative breast cancers may improve diagnostic accuracy and optimize clinical outcomes [[17], [18], [19]].

• 2)BCS as the Preferred Surgical Option

The high rate of BCS performed in the study cohort (83.9 %) reflects the feasibility and effectiveness of this approach in patients with TCCRP. Given its typically small tumor size (mean 10.4 mm) and low axillary lymph node involvement rate (5.9 %), BCS should be considered the first-line surgical treatment for localized TCCRP for patients with indications for breast conservation, especially when clear surgical margins can be achieved. This approach aligns with international breast cancer treatment guidelines that recommend breast conservation for small, low-risk tumors. The excellent locoregional control and minimal recurrence observed in TCCRP patients further support BCS as the standard surgical procedure. For patients with multifocal disease, larger tumors, or strong personal preferences for more extensive surgery, mastectomy remains a viable alternative. Incorporating intraoperative frozen-section evaluation could further enhance margin assessment, ensuring complete resection in patients undergoing BCS [20].

• 3)Potential for Reduced Adjuvant Therapy

The study's findings suggest that adjuvant therapy could be minimized in TCCRP patients due to the tumor's low proliferative activity, minimal recurrence risk, and favorable overall survival outcomes. Hormonal therapy (HT) should be limited to patients with estrogen receptor (ER)-positive tumors, which were found in only 7.7 % of cases in this study. The routine use of chemotherapy (CT) may be avoided, except in patients with high-risk features such as large tumor size (>2 cm), extensive nodal involvement, or high Ki-67 proliferation index. Similarly, radiotherapy (RT) could be selectively administered following breast-conserving surgery for patients with close or positive margins or multifocal tumors. Avoiding unnecessary adjuvant therapies could reduce treatment-associated toxicities and improve patients' quality of life without compromising clinical outcomes. Future research should explore risk-adapted adjuvant treatment algorithms specifically tailored for TCCRP [21,22].

• 4)Personalized Treatment Approach Based on Molecular Findings

The frequent detection of IDH2 R172 and PIK3CA mutations in TCCRP supports the potential application of molecular-targeted therapies, which could expand treatment options for patients with aggressive or recurrent disease. Although no patients in the present study received targeted therapy due to the lack of established clinical guidelines, these mutations offer promising therapeutic targets. IDH2 inhibitors such as enasidenib have already shown efficacy in treating IDH2-mutated cancers such as acute myeloid leukemia (AML), suggesting that these agents could be repurposed for TCCRP. Similarly, PI3K/AKT/mTOR pathway inhibitors could be explored, given the critical role of PIK3CA mutations in driving tumorigenesis. Future clinical trials should evaluate these targeted therapies either alone or in combination with conventional treatments, particularly for cases exhibiting aggressive features, recurrent disease, or resistance to standard chemotherapy. Combining targeted therapies with immune checkpoint inhibitors could further enhance treatment efficacy by overcoming immunosuppressive mechanisms in the tumor microenvironment. Establishing molecular-targeted treatment protocols would mark a significant advancement in the personalized management of TCCRP [[23], [24], [25]].

5.2. Limitations and future directions

The present study sheds light on TCCRP as a distinct subtype of breast cancer with unique histological and molecular features. However, several limitations must be acknowledged, and future research directions are proposed to address these gaps and enhance the understanding of this rare entity.

• 1)Limited Case Number and Study Heterogeneity

The major limitation of this study lies in the relatively small number of reported cases (n = 91) included in the literature review. This limitation is inherent to the rarity of TCCRP and its relatively recent recognition as a distinct breast cancer subtype. The reliance on retrospective case reports and small case series introduces considerable heterogeneity in clinical data, diagnostic criteria, and treatment approaches. Variations in the reporting of histological features, immunohistochemical results, molecular profiling, and follow-up durations further complicate the interpretation of aggregated data. Additionally, inconsistencies in therapeutic management, particularly regarding the extent of surgery and the use of adjuvant therapies, limit the generalizability of conclusions. Larger, more standardized datasets are essential to draw definitive conclusions regarding the optimal diagnostic and treatment strategies for TCCRP.

• 2)Limited Follow-up Data and Short Follow-up Duration

One significant limitation of the present study is the incomplete follow-up data for many cases, with some reports providing minimal or no long-term follow-up information. Additionally, the median follow-up time of 35.8 months is relatively short, potentially underestimating the true recurrence risk of TCCRP. Notably, the only two patients who experienced recurrence had follow-up durations equal to or longer than the median, suggesting that late recurrences may occur. Given TCCRP's indolent nature, extended follow-up periods beyond five years may be necessary to fully understand its long-term biological behavior. Future research should prioritize longer-term follow-up studies with standardized survival endpoints to clarify the recurrence patterns and optimize patient management strategies.

• 3)Need for Multi-Center, Prospective Studies

To overcome the limitations posed by small, heterogeneous retrospective datasets, future research should focus on prospective, multi-center cohort studies and clinical trials with clearly defined inclusion criteria and uniform diagnostic and therapeutic protocols. Establishing international collaborations involving specialized breast cancer centers could facilitate the collection of a more extensive, high-quality dataset. These prospective studies should include comprehensive clinical, pathological, and molecular profiling, supported by long-term follow-up data. Specific attention should be given to defining standardized diagnostic criteria based on histopathological features and genetic mutation profiles such as IDH2 R172 and PIK3CA. Uniform guidelines for surgical treatment, adjuvant therapy, and follow-up protocols should also be established to enable more robust prognostic evaluations and treatment recommendations. Longitudinal studies with a minimum follow-up of 5–10 years are critical for confirming the long-term recurrence risk and survival outcomes of patients with TCCRP.

• 4)Exploring Targeted Therapies for IDH2/PIK3CA Mutations

The high prevalence of actionable genetic mutations such as IDH2 R172 and PIK3CA mutations in TCCRP underscores the need for targeted therapy development. While IDH2 inhibitors such as enasidenib have demonstrated efficacy in other malignancies such as acute myeloid leukemia (AML), their application in breast cancer remains unexplored. Similarly, PI3K/AKT/mTOR pathway inhibitors, which are approved for other breast cancer subtypes, may have therapeutic potential in TCCRP given the high mutation frequency of PIK3CA. Future clinical trials should evaluate the efficacy, safety, and tolerability of these targeted therapies alone or in combination. Combination strategies targeting multiple pathways could potentially enhance therapeutic efficacy, particularly in patients with aggressive or recurrent disease. Preclinical models, patient-derived xenografts, and organoid cultures should also be developed to investigate the biological behavior of TCCRP and assess treatment responses in a controlled research setting.

Further exploration of chromatin modifications and mitochondrial markers could provide more insights into the metabolic reprogramming of TCCRP. Given the role of IDH2 mutations in altering chromatin structure and mitochondrial function, these markers could enhance our understanding of the molecular mechanisms underlying TCCRP's indolent nature and low recurrence rates.

• 5)Role of Immunotherapy

Despite significant advances in immunotherapy for TNBC, its role in TCCRP remains unexplored. The unique molecular profile of TCCRP, characterized by frequent IDH2 and PIK3CA mutations, suggests potential immune-related vulnerabilities. Future studies should evaluate the tumor immune microenvironment of TCCRP, focusing on PD-1/PD-L1 expression, tumor-infiltrating lymphocytes (TILs), and the presence of immune-evasive mechanisms. Immunohistochemical analysis of immune checkpoint markers and gene expression profiling could reveal whether TCCRP exhibits an “immune-hot” or “immune-cold” tumor microenvironment. This information would be critical for assessing the potential responsiveness of TCCRP to immune checkpoint inhibitors such as pembrolizumab or atezolizumab, which are already approved for TNBC. Additionally, personalized immunotherapeutic approaches such as cancer vaccines, adoptive T cell therapies, or tumor-specific monoclonal antibodies could be considered in future clinical trials targeting this rare breast cancer subtype.

6. Conclusion

TCCRP represents a unique, low-grade subtype of invasive breast cancer with well-defined histological, immunohistochemical, and molecular features. Despite its TNBC classification, its indolent behavior, low recurrence rates, and high survival outcomes warrant its recognition as a distinct clinical entity with specialized management strategies. Molecular profiling has emerged as a critical component of TCCRP diagnosis and personalized treatment, but longer follow-up studies are needed to confirm this observation. The frequent detection of IDH2 R172 and PIK3CA mutations underscores the potential of molecular-targeted therapies in future clinical practice. Genetic screening should be integrated into diagnostic algorithms for suspicious TNBC cases with unusual histological features. Given the current lack of targeted therapies and limited clinical data, future research should focus on molecular-targeted and immunotherapy-based clinical trials. Standardized diagnostic criteria, international collaborations, and long-term follow-up studies are essential for advancing clinical care and establishing evidence-based guidelines for TCCRP management.

CRediT authorship contribution statement

Ye Lu: Writing – original draft, Conceptualization. Xiangyi Kong: Writing – original draft, Formal analysis, Data curation. Wenxiang Zhang: Methodology, Investigation, Conceptualization. Xiangyu Wang: Resources, Methodology. Shengbin Pei: Software, Methodology. Yi Fang: Writing – review & editing. Jidong Gao: Writing – review & editing, Methodology. Jing Wang: Writing – review & editing, Supervision.

Funding

This work was supported by the Natural Science Foundation of China (No. 82473205), and by the Natural Science Foundation of China (No. 82371842), and by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2023-I2M-2–004), and by the Shenzhen Medical Research Fund (D2402001).

Declaration of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.