Secretory carcinoma of the breast: a report of six cases with different immunophenotypes and molecular subtypes

Abstract

Aim

Secretory carcinoma is a rare and well‐recognized subtype of breast carcinoma generally associated with a favourable prognosis. Although it was initially described in young patients, it is now known to occur at any age and in both sexes. Histologically, it is characterized by a combination of solid, microcystic and tubular architectural pattern with the presence of intracellular and extracellular secretory material that provides its distinctive histological appearance. This tumour is associated with a balanced chromosomal translocation t(12;15) resulting in the ETV6‐NTRK3 gene fusion, a translocation rearrangement with well‐established oncogenic potential. Secretory carcinoma has traditionally been considered an unusual example of a triple‐negative tumour, yet with a favourable clinical outcome.

Methods and results

In this study, we report six cases exhibiting both typical histological and molecular features of secretory carcinoma, but with varying expression of HER2 and hormone receptors. An extensive immunohistochemical and molecular analysis has been performed, including in situ hybridization and gene expression assays.

Conclusion

These findings support the existence of greater variability in surrogate and intrinsic molecular subtypes within secretory carcinomas, providing potential personalized therapeutic strategies for the treatment of these patients.

Histological findings area highly suggestive of secretory breast carcinoma. Adding molecular and immunohistochemical assays we can confirm the diagnosis and demonstrate variability in molecular subtypes, improving precision in patient treatment.

Abbreviations

BC

breast cancer

EMA

epithelial membrane antigen

FFPE

formalin‐fixed paraffin‐embedded

FISH

fluorescence in situ hybridization

GIST

gastrointestinal stromal tumour

HR

hormone receptor

IHC

immunohistochemistry

NCDB

National Cancer Database

SBC

secretory breast carcinoma

SEER

Surveillance, Epidemiology, and End Results

SLNB

sentinel lymph node biopsy

TN

triple‐negative

Introduction

Secretory breast carcinoma (SBC) is a special subtype of breast cancer (BC) that was first described in 1966 by McDivitt and Stewart as ‘juvenile breast carcinoma’, based on its diagnosis in seven patients aged 3 to 15 years old. ¹ In 1980, after similar tumours were identified in adults, the term was replaced by ‘secretory breast carcinoma’. ¹ , ² SBC represents a very rare entity accounting for less than 0.05% of all cases of invasive BC. ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸

The male to female ratio is 1:30 to 1:31, based on retrospective studies from Surveillance, Epidemiology, and End Results (SEER) database and 246 patients with SBC in the National Cancer Database (NCDB), ⁵ , ⁶ with a tendency for earlier onset age in male patients.

The usual clinical presentation is a slow‐growing, well‐circumscribed and mobile lump with radiological characteristics of a benign lesion. ⁷ It is frequently associated with in situ components, which can lead to local recurrence if the lesion is not completely resected. Several prognostic factors have been proposed, including younger age of onset, tumour size less than 2 cm, absence of vascular invasion and axillary lymph node involvement, reported in up to 30% of cases. Nevertheless, SBC is considered a neoplasm with an indolent clinical course. ⁴ , ⁵ , ⁶ , ⁸

Histologically, these tumours display three different patterns: solid, tubular or microcyst, which are typically found within a single lesion. They are composed of polygonal cells with granular, vacuolated cytoplasm and a characteristic intra and extracellular eosinophilic secretory material, positive with Alcian blue and diastase‐resistant periodic acid–Schiff (PAS‐D). Nuclear atypia and mitotic activity are low. In addition to usual epithelial markers, epithelial membrane antigen (EMA) and S100 protein are frequently expressed. ⁴ , ⁵

SBCs have traditionally been classified as triple‐negative (TN) tumours based on their immunohistochemical profile—negative for oestrogen, progesterone receptors (ER/PR) and HER2. However, unlike other breast tumours with a TN phenotype, this subtype is generally associated with a favourable prognosis. ⁴ , ⁸ , ⁹ , ¹⁰ Nevertheless, low expression of ER/PR (1%–10% of tumour cell nuclei staining) or HER2 (immunohistochemistry (IHC) score of 1+ or 2+ without HER2 gene amplification demonstrated by in situ hybridization (ISH) techniques) ¹¹ , ¹² is not uncommon and recent large cohort series have suggested that SBCs may display an immunoprofile consistent with hormone receptor (HR)–positive BC, rather than the typical TN phenotype ⁵ , ⁶ , ¹³ (Table 1).

Table 1.

Secretory breast carcinoma immunoprofile: review of literature ⁵ , ⁶ , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰

Reference	Number of cases	Immunophenotype (number of cases)	Age (years)
Del Castillo M, Chibon F, Arnould L, et al. Secretory Breast Carcinoma: A Histopathologic and Genomic Spectrum Characterized by a Joint Specific ETV6‐NTRK3 Gene Fusion. Am. J. Surg. Pathol. 2015 Nov;39(11):1458–1467	11	ER−/PR−/HER2− (6) ER+/PR+/HER2− (5)
Soyer T, Yaman Bajin İ, Orhan D, et al. Secretory breast carcinoma in a 6‐year‐old girl: mastectomy with sentinel lymph node dissection. Pediatr. Surg. Int. 2015 Jul;31(7):677–681.	1	ER−/PR−/HER2−	6
Sharma V, Anuragi G, Singh SP, et al. Secretory Carcinoma of the Breast: Report of Two Cases and Review of the Literature. Case Rep. Oncol. Med. 2015;2015:581892.	2	ER−/PR−/HER2− (2)	55/12
Li G, Zhong X, Yao J, et al. Secretory breast carcinoma in a 41‐year‐old man with long‐term follow‐up: a special report. Future Oncol. 2015;11(12):1767–73.	1	NA	41
Aktepe F, Sarsenov D, Özmen V. Secretory Carcinoma of the Breast. J. Breast Health. 2016 Oct 1;12(4):174–176.	1	ER−/PR−/HER2−	24
Jacob JD, Hodge C, Franko J, et al. Rare breast cancer: 246 invasive secretory carcinomas from the National Cancer Data Base. J. Surg. Oncol. 2016 Jun;113(7):721–5.	246	ER−/PR−/HER2− (181) ER+/HER2− (64) ER+/HER2+ (1)	56, 4 (median)
Misra M, Sagar P, Friedmann AM, et al. CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 12‐2016. An 8‐Year‐Old Boy with an Enlarging Mass in the Right Breast. N. Engl. J. Med. 2016;374:1565–74.	1	NA	8
Krings G, Joseph NM, Bean GR, et al. Genomic profiling of breast secretory carcinomas reveals distinct genetics from other breast cancers and similarity to mammary analog secretory carcinomas. Mod. Pathol. 2017 Aug;30(8):1086–1099.	9	ER+/PR+/HER2− (1) ER+/PR−/HER2− (3) ER−/PR−/HER2− (5)	45 (median)
Shui R, Cheng Y, Bai Q, Yang W. Secretory breast carcinoma with a papillary‐predominant pattern: an unusual morphological variant. Histopathology. 2017 Sep;71(3):488–493.	1	ER−/PR−/HER2−	53
Garlick JW, Olson KA, Downs‐Kelly E, et al. Secretory breast carcinoma in an 8‐year‐old girl: A case report and literature review. Breast J. 2018 Nov;24(6):1055–1061.	1	ER−/PR−/HER2−	8
Ghilli M, Mariniello MD, Scatena C, et al. Male secretory breast cancer: case in a 6‐year‐old boy with a peculiar gene duplication and review of the literature. Breast Cancer Res. Treat. 2018 Aug;170(3):445–454.	1	ER−/PR−/HER2−	6
Sobrino Prados A, Eizaguirre Zarza B, Gimeno Esteras E, et al. Multicentric secretory carcinoma of the breast: Case report and review of the literature. Rev. Esp. Patol. 2020 Apr‐Jun;53(2):117–120.	1	ER−/PR−/HER2−	32
Yang Y, Wang Z, Pan G, et al. Pure secretory carcinoma in situ: a case report and literature review. Diagn. Pathol. 2019 Aug 23; 14(1):95.	1	ER−/PR−/HER2− In situ	38
Hoda RS, Brogi E, Pareja F, et al. Secretory carcinoma of the breast: clinicopathologic profile of 14 cases emphasizing distant metastatic potential. Histopathology. 2019 Aug;75(2):213–224.	14	ER−/PR−/HER2− (4) ER+/PR−/HER2− (3) ER+/PR+/HER2− (3) Unknown (4)	56 (median)
Li L, Wu N, Li F, et al. Clinicopathologic and molecular characteristics of 44 patients with pure secretory breast carcinoma. Cancer Biol. Med. 2019 Feb;16(1):139–146.	44	ER−/PR−/HER2− (28) ER+ /PR+/HER2−(16)	<30 (7) >30 (37)
Novochadlo Klüppel E, Rodrigues da Costa L, Marquetto Tognolo C, et al. Secretory breast carcinoma in a male child: Case report and literature review. Int. J. Surg. Case Rep. 2020;73:310–314.	1	ER+/HER2−	14
Banerjee N, Banerjee D, Choudhary N. Secretory carcinoma of the breast, commonly exhibits the features of low grade, triple negative breast carcinoma—A Case report with updated review of literature. Autops. Case Rep. 2020 Dec 8;11:e2020227.	1	ER−/PR−/HER2−	60
Wu IK, Lai YC, Chiou HJ, et al. Secretory Carcinoma of the Breast: A Case Report and Literature Review. J. Med. Ultrasound 2021;29: 57‐59.	1	ER−/PR−/HER2−	26
Tang H, Zhong L, Jiang H, et al. Secretory carcinoma of the breast with multiple distant metastases in the brain and unfavourable prognosis: a case report and literature review. Diagn. Pathol. 2021 Jun 24;16(1):56.	1	ER‐/PR−/HER2−	39
Gong P, Xia C, Yang Y, Clinicopathologic profiling and oncologic outcomes of secretory carcinoma of the breast. Sci. Rep. 2021 Jul 19;11(1):14738.	190	ER+ (58) PR+ (40)	56 (median)
Lian J, Wang LX, Guo JH, et al. Secretory breast carcinoma in a female adult with liver metastasis: a case report and literature review. Diagn. Pathol. 2021 Oct 10;16(1):89.	1	ER−/PR−/HER2−	34
Chen M, Pu T, Wei B, et al. Genomic landscape of secretory carcinoma of the breast with axillary lymph node metastasis. Pathol. Res. Pract. 2022 Mar;231:153790.	21	ER+/PR+/HER2− (7) ER+/PR−/HER2− (6) ER−/PR−/HER2− (8)	43 (median)
Lei T, Yang Y, Shi Y, et al. Clinicopathological features and genomic profiles of a group of secretory breast carcinomas in which progressive cases have more complex genomic features. Diagn. Pathol. 2022 Dec 31;17(1):101.	7	ER+/PR−/HER2− (3) ER−/PR−/HER2− (4)	39 (median)
Deng L, Li Y, Zhong J. Secretory breast cancer in a boy: A case report with genetic analysis using next‐generation sequencing and literature review. Medicine (Baltimore). 2023 Jul 7;102(27):e34192.	1	ER−/PR−/HER2−	5
Shi L, Zhang Y, Wu J, et al. A case report and literature review on a rare subtype of triple‐negative breast cancer in children. BMC Pediatr. 2023 Sep 29;23(1):494.	1	ER+/PR−/HER2−	8
Mouadin A, Tahiri El Ousrouti L, et al. Secretory Breast Carcinoma: Report of Two Cases and Literature Review. Clin. Med. Insights Case Rep. 2023 Oct 31;16:11795476231209182.	2	ER−/PR−/HER2− (1) ER+/PR−/HER2− (1)	42/ 48
Sanli AN, Tekcan Sanli DE, et al. Secretory Carcinoma of Breast: A Population‐Based Study. Am. Surg. 2024 Feb;90(2):252–260.	70	ER+/PR+/HER2− (24) ER+/PR−/HER2− (48) RH+/HER2+ (3) RH−/HER2+ (1)	57 (mean)
Zhao YY, Ge HJ, Yang WT, et al. Secretory breast carcinoma: clinicopathological features and prognosis of 52 patients. Breast Cancer Res. Treat. 2024 Feb;203(3):543–551.	52	ER+/PR+/HER2− (9) ER+/PR−/HER2− (8) ER−/PR−/HER2− (34) ER−/PR−/HER2+ (1)	46 (median)
Qi M, Gao S, Zhang Z, et al. Secretory breast carcinoma: a multicenter clinicopathologic study of 80 cases with emphasis on prognostic analysis and chemotherapy benefit. Breast Cancer Res. Treat. 2025 Apr;210(2):451–461.	80	ER+ (42) PR+ (30) HER+ (6)	5, 48 (median)
Ren H, Tong W, Ma J, et al. Secretory breast carcinoma: morphologic and molecular heterogeneity with indicators of aggressive potential in a cohort of 29 cases. J. Pathol. Clin. Res. 2025 Nov;11(6):e70060.	29	ER−/PR−/HER2− (13) ER+ and/or PR+/HER2− (16)	44 (median)

ER, Oestrogen receptor; HER2, Human epidermal factor receptor 2; NA, Not available; PR, Progesterone receptor.

The association between SBC and a balanced chromosomal translocation, t(12;15), has been described. This translocation results in the ETV6‐NTRK3 gene fusion that activates Ras‐MAP kinase and PI3K‐Akt signalling pathways, drivers of cell proliferation and survival, thereby promoting carcinogenesis ¹⁴ , ⁴¹ , ⁴²

An IHC technique is now available for the rapid determination of fusions involving the kinase domain of NTRK1, 2 or 3, known as pan‐TRK immunohistochemistry. Although some authors have raised concerns regarding its accuracy to identify the presence of NTRK1‐3 fusions, particularly due to a high false‐negative rate (up to 18%) and significant variability depending on the monoclonal antibody clone used, this assay could be a good option as a screening tool. ⁴³

In recent years, clinical trials have focused on therapies targeting specific molecular alterations, with NTRK fusion‐positive tumours demonstrating promising outcomes. TRK inhibitor (TKI)‐targeted therapy for patients with NTRK fusion‐positive tumours, including SBC, has shown high response rates. First‐generation TKIs such as larotrectinib and entrectinib have been associated with significant clinical benefit. Cases of patients with SBCs harbouring ETV6‐NTRK3 fusion successfully treated with larotrectinib have been reported, achieving strong clinical response with sufficient tolerance and minimal adverse effects. ⁴⁴ , ⁴⁵ , ⁴⁶

Based on these findings, international guidelines for biomarker testing in BC now recommend screening for NRTK fusions in patients with advanced or metastatic cancer. ⁴⁷ , ⁴⁸ This study must be performed at least in all BC showing features consistent with the secretory histological subtype, regardless of their immunophenotype.

Given the lack of consensus regarding ER, PR and HER2 status in SBC, and the relevance of achieving an accurate and precise diagnosis for this rare cancer subtype, we present a well‐characterized series including six cases of SBC, displaying diverse immunophenotypic profiles, with significant implications for personalized treatment strategies.

Material and Methods

Case Selection and Classification

Six cases of SBC diagnosed between 2016 and 2024 were retrieved from the surgical pathology archives of four institutions: Hospital Universitario Virgen del Rocío, Hospital Universitario Virgen de Valme, Hospital de Jerez and Hospital Miguel Servet.

All available pathology reports and haematoxylin‐and‐eosin (H&E)‐stained slides were independently reviewed by two pathologists (B.V. and M.A.L.) to confirm the diagnosis of secretory carcinoma based on established morphologic features. A tumour was classified as secretory carcinoma when it exhibited: (1) A microcystic, tubular or solid growth patterns; (2) polygonal tumour cells, with vacuolated pale‐pink cytoplasm, resistant to diastase PAS (Periodic acid–Schiff) stain; (3) small, round and cytologically bland nuclei; (4) minimal to moderate nuclear atypia and low to moderate mitotic activity; (5) detection of ETV6 rearrangement gene (12p13) by fluorescence in situ hybridization (FISH), in at least 10% of tumour cells (Figure 1).

Figure 1.

Histological features and immunohistochemical and FISH assay. (A) Case 2: Secretory breast carcinoma with glandular pattern (HE) (B) Case 1: HER2 IHC (clone 4B5 Ventana Roche): score 3+; (C) Case 1: HER2 (silver in situ hybridization) (ratio HER2/CEP17= 2,4/Average Number of HER2 Signals = 4, 5); (D): Case 1: Secretory breast carcinoma showing intracellular and extracellular eosinophilic material (HE); (E) Case 1: Paget disease (HE); (F) Paget disease: CK7 immunostaining; (G) Case 4: Secretory breast carcinoma with microcystic pattern (HE); (H) Intracellular and extracellular diastase‐resistant secretions (Periodic acid–Schiff–Diastase: PAS‐D); (I) Case 2: ETV6 rearrangement gene (12p13): fluorescence in situ hybridization (FISH).

Clinical data, including presentation, stage, treatment and follow‐up, were collected when available and summarized in Table 1.

Immunohistochemical Analysis

Immunohistochemistry was performed on 5‐μm formalin‐fixed paraffin‐embedded (FFPE) tumoral tissue sections. The following antibodies were used: anti‐Oestrogen Receptor (ER, clone SP1) Rabbit Monoclonal Primary Antibody, anti‐Progesterone Receptor (PR, clone 1E2) Rabbit Monoclonal Primary Antibody, VENTANA anti‐HER2/neu (clone 4B5) Rabbit Monoclonal Primary Antibody, anti‐Ki‐67 (clone 30‐9) Rabbit Monoclonal Primary Antibody, anti‐S100 (clone 4C4. 9) Primary Antibody and pan‐TRK (EPR17341, Rabbit Monoclonal Antibody, Ventana Roche). Staining was performed on a BenchMark XT automated tissue staining system (Ventana Medical Systems, AZ) using validated protocols (Figure 1).

Fluorescence In Situ Hybridization (FISH)

Dual colour FISH was performed to identify the presence of an ETV6 gene rearrangement using the commercial break‐apart Vysis ETV6 Break Apart FISH Probe Kit (Abbot®, Chicago, IL). A normal nucleus usually shows at least two fusion signals while a case positive for rearrangement of ETV6 shows one fusion and a pair of split orange and green signals. The orange probe spans the 5′ telomeric end of the ETV6 gene from intron 2 and the green probe flanks the 3′ centromeric end region of the ETV6 gene, respectively. A minimum of 100 interphase nuclei were screened for each of the cases, and the cut‐off value for positive ETV6 rearrangement was a minimum of 10% of all analysed cells.

Prosigna® Assay

The Veracyte Prosigna® assay measures the expression levels of 50 target genes plus eight constitutively expressed normalization genes. This prognostic signature assay for BC uses the PAM50 gene signature, an in vitro diagnostic assay that, based on the gene expression profile, categorizes the tumour into luminal A, luminal B, basal‐like and HER2‐enriched subtypes according to intrinsic molecular BC subtypes classification. ⁴⁹

Prosigna assays were performed from FFPE tumour samples from surgical resection specimens previously selected by pathologists and manually macro‐dissected from unstained tissue sections.

RNA was extracted from slide‐mounted breast tissue sections using Roche® FFPET RNA Isolation Kit following the specifications indicated by the manufacturer and by the Prosigna Insert.

Extracted RNA samples, meeting quality and concentration specifications, were directly hybridized (without reverse transcription or amplification) using gene‐specific probe pairs. After hybridization, all of the sample purification steps are automated on the nCounter Prep Station where the probe/target complexes are aligned and immobilized in the nCounter cartridge. Finally, the cartridge is placed in the nCounter Digital Analyser for data collection.

Results

Clinicopathologic Features

The clinicopathologic characteristics of the six cases, including immunohistochemical assay, are summarized in Tables 2 and 3. All the patients were females with ages ranging from 33 to 66 years (mean: 52, median: 50 years). The cohort included both premenopausal and postmenopausal women in similar proportions.

Table 2.

Clinicopathological features, including type of therapy and follow‐up

	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Age	66	51	49	33	49	67
Menopause	Yes	Yes	No	No	No	Yes
Tumour size	14 mm	12 mm	8 mm	22 mm	22 mm	34 mm
Unifocal/multifocal	Multifocal	Unifocal	Unifocal	Multifocal	Unifocal	Unifocal
In situ carcinoma/Paget disease	Paget disease	No	No	In situ	No	Yes
Vascular invasion	No	No	No	No	Yes	No
Type of surgery	Radical	Conservative	Conservative	Radical	Conservative	Conservative
SLNB/axillary dissection	SLNB	SLNB	SLNB	SLNB	SLNB	SLNB
Axillary status	N1mi‐sn	N0‐sn	N0‐sn	N0‐sn	N1mi‐sn	N0‐sn
Tumour stage	IB	IA	IA	IIA	IB	IIA
Adjuvant therapy	Anti HER2 + ChT+ RT	ChT + RT	RT + HT	RT	ChT + RT	RT + HT
Follow‐up	Liver and CNS metastases	No events	No events	No events	No events	No events

ChT, Chemotherapy; CNS, Central nervous system; HT, Hormone therapy; RT, Radiotherapy; SLNB, Selective lymph node biopsy; sn, Sentinel node.

Table 3.

Immunohistochemical staining of six secretory breast carcinomas

	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
ER (SP1, Ventana‐Roche)	− (<1%)	− (<1%)	+ (50%–60%)	+ (2%–10%) (Low expressor)	+ (2%–10%) (Low expressor)	+ (10%–15%)
PR (1E2, Ventana Roche)	− (<1%)	− (<1%)	− (<1%)	+ (15%–20%)	+ (2%–10%) (Low expressor)	(<1%)
HER2 (4B5 Pathway, Ventana‐Roche)	3+	0	0	0	0	0
S100 (4C4. 9, Ventana Roche)	+	+	+	+	+	+
Ki67 (30‐9, Ventana Roche)	15%–20%	15%–20%	6%–10%	6%–10%	15%–20%	10%–15%
pan‐TRK (EPR17341, Ventana Roche)	+/− (focal)	+/− (focal)	+/− (focal)	+	+/− (focal)	+
FISH (ETV6‐NTRK3)	30%	62%	100%	79%	92%	90%
PAM 50	HER2‐enriched	Invalid result	Luminal A	Luminal A	Luminal A	Luminal A

ER, PR and HER2 immunostaining were evaluated following international recomendations. ²¹ , ²²

ER, Oestrogen receptor; FISH, Fluorescent in situ hybridization; HER2, HER2‐neu; Ki67, Proliferation index; PAM50, Prosigna Breast Cancer Prognostic Gene Signature Assay®; pan‐TRK, Tropomyosin receptor kinase (TRK) proteins A, B and C; PR, Progesterone receptor; S100, S100 protein.

The initial diagnosis was established on excision or core needle/vacuum‐assisted biopsy performed on a palpable mass or radiologically detected lesions. Two out of six patients showed clinical symptoms, one with a nipple cutaneous lesion and another with a palpable nodule, respectively.

Tumour size ranged from 8 to 34 mm, being multifocal in two out of six tumours. One case was associated with Paget disease of the nipple and two cases included in situ carcinoma in addition to the invasive carcinoma. Lymphovascular invasion was identified in one case, which also showed sentinel lymph node micrometastasis.

All patients were subjected to primary surgical treatment with sentinel lymph node biopsy (SLNB), and all of them received different adjuvant treatments. Three out of the six patients were treated with anthracycline and taxane‐based chemotherapy regimens, either currently or sequentially, one in combination with trastuzumab due to HER2 positivity. Two patients were treated with hormonal therapy alone, and all of them underwent local radiotherapy as adjuvant treatment.

Follow‐up data showed that one patient (Case 1) developed liver and central nervous system metastases, while the remaining patients were disease‐free at last follow‐up.

Discussion

Secretory breast carcinoma is an exceptionally rare breast neoplasm, which represents <0.05% of all BC. ³ , ⁴ , ⁸ While traditionally considered an indolent carcinoma predominantly affecting children and young patients, recent evidence indicates that it can occur across all age groups and may exhibit a more heterogeneous clinical behaviour. Notably, cases arising in older patients have been reported to demonstrate a prognosis comparable to that of conventional BC, ³ , ⁴ , ⁵ , ⁶ , ⁸

Regarding clinicopathological features and prognosis, our series reflects this variability; most patients experienced favourable outcomes; however, one developed liver and CNS metastasis. Tumour size at presentation was small to intermediate (8–34 mm), and multifocality was observed in two cases, consistent with what has been previously published. ⁵ , ⁶ , ³³ Lymphovascular invasion and nodal involvement, although infrequent, were identified, confirming that metastatic potential exists. Paediatric cases usually are characterized by an excellent prognosis with conservative surgery alone; however, there is no consensus in adults in terms of the use of adjuvant endocrine and/or chemotherapy even in the presence of axillary metastasis.

The use of new drugs targeted to NTRK‐fusion tumours, characteristic of this BC special subtype, is under debate, but cases with successfully response have been documented. ⁴⁴ , ⁴⁵ , ⁴⁶

Within adults, surgery constitutes the treatment of election either as breast‐conserving or radical, depending on tumour size and/or focality; some studies recommend wider resection margins and the use of adjuvant radiotherapy to minimize local recurrence. ⁵⁰ SLNB is recommended for axillary staging. In our series, all patients underwent SLNB, with micro metastasis identified in two cases. The role of systemic therapy is less clearly defined. Although chemotherapy is frequently administered in accordance with international guidelines for BC, its benefit in SBC remains unclear. Endocrine therapy could be considered in HR‐positive tumours, while HER2‐positive cases have been managed with anti‐HER2 therapies, such as one patient in our series. This therapeutic heterogeneity highlights the lack of standardized management protocol and the need for individualized treatment strategies.

Historically SBC has been classified among the TNBC, due to the frequent lack or low expression of ER, PR and HER2. ⁶ , ⁹ , ¹⁰ , ¹³ Therefore, accurate biomarker assessment becomes particularly critical in cases with low expression, where subtle differences in staining interpretation may have relevant biological and therapeutic implications. In this context, AI‐assisted digital pathology may enhance the robustness and reproducibility of biomarker evaluation and improve the precision of quantification. Moreover, a subset of BC with TN immunophenotype are included in the basal‐like intrinsic subtype, defined by Perou et al. ⁴⁹ characterized by the expression of markers presented in normal myoepithelial cells of the mammary tissue. Different studies have demonstrated the expression of most of these basal/myoepithelial markers such as CK5/6, EGFR, CD117 (ckit), vimentin and S‐100 protein in the SBC; these findings would confirm a basal nature of this special type of BC; nevertheless, the clinical course of SBC is often less aggressive than that of conventional basal‐like carcinomas, suggesting that additional molecular mechanisms may modulate tumour behaviour. ⁹ , ¹⁰ , ⁴²

In contrast to the conventional view of SBC as a uniformly TN entity, Diallo et al. ⁵¹ reported findings that challenge this paradigm. In a series of 13 SBCs, HER2 evaluation using immunohistochemistry and in situ hybridization identified one HER2‐positive tumour (3+ by immunohistochemistry) and one equivocal case (2+) with confirmed HER2 amplification by FISH. These observations raise the possibility that a HER2‐positive immunoprofile may define a distinct subset within SBC. Notably, the clinical behaviour of these patients resembled that of HER2‐amplified BC rather than conventional SBCs, highlighting the potential relevance of HER2‐targeted therapeutic strategies in this subset of tumours. Subsequent series have also demonstrated immunoprofiles consistent with HR‐positive tumours, although typically with low levels of expression. ⁵ , ⁶ , ⁸ , ¹³ , ¹⁴ , ²⁰ , ²⁵ , ²⁶ , ³² , ³³ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ In our series, one tumour exhibited unequivocal HER2 positivity, demonstrated by IHC and in situ hybridization techniques, while four additional cases showed low ER and/or PR expression and therefore meet de criteria for ‘low expressors’ according to current classifications. ¹¹ Interestingly, the HER2‐positive tumour demonstrated a proliferative index lower than the expected for HER2‐driven disease. Only one case exhibited a pure TN phenotype. These findings support the concept that SBC is not a homogeneous TN entity but rather a morphologically distinctive tumour with diverse phenotypes, including luminal A and HER2‐positive subtypes.

With the aim to support this molecular heterogeneity in SBC, we performed the study of gene expression profile using the PAM50 gene signature. The results confirm the variability in molecular intrinsic subtypes in SBC, with a predominant luminal subtype (66%) and a case with a HER2‐enriched profile. This may impact the management of this type of BC, expanding treatment options beyond conventional chemotherapy to include targeted anti‐HER2 therapy or endocrine therapy when appropriate.

The pathognomonic hallmark of SBC is the balanced translocation t(12;15) (p13;q25), resulting in the ETV6‐NTRK3 gene fusion, firstly described by Togton et al. ⁴⁰ , ⁴¹ This rearrangement is also observed in congenital fibrosarcoma, mesoblastic nephroma, mammary analogue secretory carcinoma of salivary glands, acute myeloid leukaemia, gastrointestinal stromal tumour (GIST), some thyroid carcinoma and other infantile tumours. ¹⁴ , ⁴¹ , ⁴² , ⁴⁶ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ This rearrangement fuses sequences encoding the sterile α motif (SAM) domain of the ETS transcription factor, ETV6 (TEL), to the protein tyrosine kinase (PTK) domain of the neurotrophin‐3 receptor, NTRK3 (TRKC). ⁵⁶ The SAM domain promotes ETV6‐NTRK3 polymerization and subsequent ligand‐independent PTK activation. Bratthauer GL et al. suggest that this characteristic fusion causes phosphorylation of the mammary growth factor (STAT5a), constitutively activating it and giving it the characteristic appearance. ⁵⁷ Importantly, this fusion has not been identified in other histologic subtypes of BC, making it a highly specific diagnostic biomarker. ⁴² , ⁵⁶

In our series, all cases demonstrated ETV6 rearrangement by FISH, confirming its diagnostic value. While pan‐TRK immunohistochemistry has been proposed as a screening tool, its sensitivity and specificity are insufficient to replace molecular assays. In our cohort, diffuse staining was observed in four cases and focal staining in two. Consequently, when morphology raises suspicion of SBC, confirmatory testing by FISH, RT‐PCR or next‐generation sequencing is recommended to ensure diagnostic accuracy.

ETV6‐NTRK3 also associates important therapeutic implications. The development of TRK inhibitors, such as larotrectinib and entrectinib, has expanded treatment opportunities for patients with advanced or metastatic SBC harbouring this fusion. ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁵⁸

In conclusion, SBC is a rare but distinct BC characterized by unique morphological features and the pathognomonic ETV6‐NTRK3 fusion. Although prognosis is generally favourable, evidence from our series and others indicates that a subset of patients may be associated with aggressive clinical outcomes, particularly in adults, highlighting the biological heterogeneity of this tumour. Phenotypic diversity—including Luminal A‐like and HER2‐enriched intrinsic subtypes—expands therapeutic possibilities incorporating endocrine and anti‐HER2 therapies when appropriate. Furthermore, the identification of NTRK gene fusions reveals opportunities for targeted therapy in advanced disease.

Accurate diagnosis of SBC therefore requires an integrated approach combining morphology, immunohistochemistry and molecular testing. This strategy ensures correct classification of this rare tumour and facilitates personalized therapeutic options with the potential to improve clinical outcomes.

Author contributions

BV and MAL‐G conceptualized the project, collected data, performed literature review, wrote and revised the manuscript. LG, BM, BE and JMM contributed cases and edited the manuscript. MB perform molecular assay and reviewed the manuscript. MB reviewed clinical and follow‐up data and reviewed the manuscript. All authors approve the final version of the manuscript, figures and supplementary material for publication.

Funding information

Additional funding has not been received for this study.

Conflict of interests

The authors declare no conflicts of interest in relation to the subject matter discussed in this manuscript.

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.