Primary adenoid cystic carcinoma of the breast: a clinicopathological case series

Abstract

Adenoid cystic carcinoma of the breast (ACCB) is a rare special-type carcinoma, accounting for <0.1% of breast malignancies. Despite its frequent triple-negative phenotype, ACCB typically demonstrates indolent behavior and a favorable prognosis. Owing to its rarity and overlapping radiologic and histopathological features, accurate diagnosis can be challenging. We retrospectively analyzed three cases of histologically confirmed primary ACCB diagnosed at a tertiary care center. Clinical presentation, imaging findings, histomorphology, immunohistochemistry, treatment, and follow-up data were reviewed. The patients were women aged 42–58 years, all presenting with a breast lump; one case showed Paget-like nipple changes. Imaging findings varied from benign-appearing cysts to Breast Imaging Reporting and Data System (BI-RADS) category 4 lesions. Histology revealed classic biphasic morphology with tubular, cribriform, and focal solid patterns with perineural invasion noted in one. Tumor cells consistently expressed c-KIT (CD117) and myoepithelial markers (p63/S100), lacked HER2 (human epidermal growth factor receptor 2) expression, and showed variable hormone receptor status. All tumors were low-grade (grade 1), ≤2 cm, with negative sentinel lymph nodes where assessed. Surgical excision with clear margins was performed in all cases, with adjuvant radiotherapy in one patient. No recurrence or metastasis was observed on follow-up. Primary ACCB requires accurate recognition to prevent misdiagnosis and overtreatment.

INTRODUCTION

Adenoid cystic carcinoma (AdCC) of the breast is a rare malignancy, accounting for fewer than 0.1% of all breast cancers [1]. These are among the most common salivary gland malignancies but also affect other exocrine tubulo-acinar glands such as the breast [2]. Adenoid cystic carcinoma of the breast (ACCB) typically affects women in their sixth to seventh decade of life and is characterized by a slow-growing, indolent course with a generally favorable prognosis [3]. ACCB is primarily composed of glandular epithelial, myoepithelial, and basaloid cells arranged in classic tubular, sieve-like, or solid structures. Invasive growth is commonly observed under a microscope, and some tumors exhibit perineural invasion [4].

In this report, we present a clinicopathological series of three cases of primary ACCB, emphasizing their varied clinical and radiological presentations (Table 1). Table 2 shows key differences between clinicopathological features of ACCB and conventional invasive ductal carcinoma.

Table 1.

Summary of clinicopathological features

Age (yr)/sex	ER/PR/HER2	TNM stage	Ki-67 (%)	Surgery	Adjuvant therapy	Outcome
58/F	ER−, PR−, HER2−	pT1c Nx	5–7	WLE	None	No evidence of disease, patient remains on follow-up
42/F	ER−, PR−, HER2−	pT1c N0(sn)	25–28	WLE+SLNB	Radiotherapy	No evidence of disease, patient remains on follow-up
54/F	ER−, PR+, HER2−	pT1c N0	15–18	WLE+SLNB	None	No evidence of disease, patient remains on follow-up

ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; F, female; WLE, wide local excision; SLNB, sentinel lymph node biopsy.

Table 2.

Key differences between adenoid cystic carcinoma of the breast and conventional IDC

Feature	Adenoid cystic carcinoma of the breast	Invasive ductal carcinoma (IDC, NST)
Epidemiology
Incidence	<0.1% of all breast cancers	70%–80% of all invasive breast cancers
Age at diagnosis	Median 50–64 years (range, 25–80)	Median, 62 years
Clinical features
Presentation	Palpable, firm, discrete mass; may be tender or painful (perineural involvement common)	Palpable mass; may present with skin changes, nipple retraction, or axillary lymphadenopathy
Growth pattern	Slow-growing, often well-circumscribed; 25% have macroscopic cystic areas	Infiltrative, irregular growth with desmoplastic reaction
Axillary lymph nodes	Rarely involved (5%–10%)	Common site of metastasis; 30%–40% at presentation
Radiology
Mammography	Round/oval shape (78%–93%), circumscribed margins (36% of lesions), often mimics benign lesion	Irregular/spiculated shape, indistinct or spiculated margins, associated architectural distortion
Ultrasound	Round/oval, parallel orientation (81%), isoechoic or hyperechoic (62.5%)–unusual for malignancy; cyst-like echogenicity reported; half are avascular on Doppler	Hypoechoic, irregular, taller-than-wide, posterior acoustic shadowing, hypervascular
MRI	High T2 signal (87.5%), restricted diffusion (71%), homogeneous enhancement (62.5%); circumscribed margins in 50%	Irregular margins, rim enhancement, rapid washout kinetics
Histopathology
Architecture	Cribriform, tubular, trabecular, or solid patterns; biphasic cell population (epithelial+myoepithelial)	Glands, trabeculae, or sheets; no myoepithelial component; desmoplastic stroma
Lumens	Two types: true glandular lumina+pseudolumens containing basement membrane material (eosinophilic cylinders)	True glandular lumina only
Cell types	Dual: luminal/ductal epithelial cells (CK7+)+myoepithelial/basaloid cells (p63+, calponin+, SMMHC+)	Single epithelial cell population
Nuclear grade	Low to intermediate (classic variant); high in solid-basaloid subtype	Ranges from low to high grade
Perineural invasion	Common (does not imply poor prognosis as in other sites)	Uncommon; when present, may indicate aggressive behavior
Immunohistochemistry&molecular
ER/PR/HER2	Triple-negative (>95% of cases)	Heterogeneous: 70%–80% ER+, 15%–20% HER2+, 10%–15% triple-negative
CD117/c-KIT	Strongly positive (membranous) in most cases	Usually negative
p63/p40	Positive (nuclear) in myoepithelial/basaloid cells	Negative (except in some metaplastic carcinomas)
MYB	Overexpressed (often due to MYB::NFIB fusion)	Not overexpressed
Genetic fusion	MYB::NFIB fusion, t(6;9)(q22–23;p23–24), in the majority of cases	No consistent fusion; complex karyotypes
Molecular subtype	Basal-like but with lower genetic instability than conventional basal-like TNBC	Luminal A/B, HER2-enriched, or basal-like
Prognosis&outcomes
5-Year relative survival	98.1%	90% (stage I) to 20%–30% (stage IV)
Local recurrence	Low; adjuvant radiation may further reduce risk	Varies by subtype and treatment
Distant metastasis	Rare in classic type; can occur late (years to decades); solid-basaloid subtype more aggressive	Common in high-grade subtypes; usually within 3–5 years (TNBC) or later
Chemo-responsiveness	Chemo-resistant; neoadjuvant chemotherapy shows 0% pathologic complete response rate	Variable; responsive in high-grade and proliferative subtypes

IDC, invasive ductal carcinoma; NST, no special type; MRI, magnetic resonance imaging; CK, cytokeratin; SMMHC, smooth muscle myosin heavy chain; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; TNBC, triple-negative breast cancer.

CASE REPORT

Case 1

A 58-year-old woman presented in 2023 with a left breast lump; initial ultrasound suggested benignity and mammography showed bilateral cystic changes. Two years later, a surveillance mammogram revealed a new opacity seen in right breast central quadrant on craniocaudal view (Fig. 1A). Ultrasound revealed a complex cystic lesion in the right breast (6 o’clock position, circle 1, zone B) with thin septations and no internal vascularity (Fig. 1B), classified as Breast Imaging Reporting and Data System (BI-RADS) category 4. Ultrasound-guided core biopsy showed a well-circumscribed neoplasm composed of tubules and trabeculae lined by cuboidal cells and surrounding myoepithelial cells and abundant basement membrane material. Focal mucinous material was seen. A diagnosis of a benign neoplasm favoring adenomyoepithelioma with abundant basement membrane matrix was made, and the patient was advised to undergo wide local excision to rule out malignancy. Histopathology demonstrated a biphasic tumor with tubular and trabecular architecture, composed of inner ductal epithelial cells and outer myoepithelial cells with abundant basement membrane-like material (Fig. 1C-E). Immunohistochemistry (IHC) showed membranous c-KIT (CD117) positivity (Fig. 1F), S100 and p63 positivity in myoepithelial cells and pan-cytokeratin in epithelial cells (Fig. 1G–J). Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) were negative. Final diagnosis of invasive breast carcinoma, AdCC, grade 1 (pT1c Nx) was given. Margins were clear, and the patient remains recurrence-free on continuous follow-up.

Fig. 1.

Case 1. A 58-year-old woman with adenoid cystic carcinoma of the breast (ACCB). (A) Mammogram (craniocaudal view) showing a new opacity in the right breast central quadrant. (B) Ultrasound revealing a corresponding complex cystic lesion with thin septations and no internal vascularity. (C) Hematoxylin and eosin (H&E) stained section showing tumor islands of ACCB (×40). (D) H&E-stained section showing tubular and trabecular architecture lined by inner ductal and outer myoepithelial cells (×200). (E) H&E-stained section showing abundant basophilic basement membrane–like material (×400). (F) Immunohistochemistry showing strong membranous positivity for c-KIT (CD117) in the epithelial component (×400). (G) CK5/6 positivity in the myoepithelial cell layer (×400). (H) p63 nuclear positivity highlighting the myoepithelial cells (×400). (I) Pan-cytokeratin positivity in the epithelial cells (×100). (J) S100 positivity in the myoepithelial component (×400).

Case 2

A 42-year-old woman with a history of left breast carcinoma treated with breast-conserving surgery in 2024 presented with a new 2 cm subareolar lump and Paget-like nipple changes. The patient had a biopsy and IHC confirmed ACCB (triple-negative, c-KIT+, Ki-67 25%–28%) from outside. We could not retrieve slides or blocks for the same. The patient presented to our center for further management. Mammogram showed an architectural distortion with surgical clips in the left breast central quadrant (Fig. 2A). Corresponding ultrasound showed a parenchymal architectural distortion in the left breast 6 o’clock position with no vascularity, due to post-surgical changes (Fig. 2B). She underwent wide local excision with sentinel lymph node biopsy. Histology revealed cribriform and trabecular patterns with focal solid areas (15%–20%) (Fig. 2C–E) and perineural invasion (Fig. 2F). Sentinel lymph nodes were negative. The final diagnosis was ACCB, Grade 1 (pT1c N0(sn)). Adjuvant radiotherapy was administered. No recurrence has been observed on follow-up.

Fig. 2.

Case 2. A 42-year-old woman with recurrent adenoid cystic carcinoma of the breast. (A) Mammogram showing architectural distortion with surgical clips in the left breast central quadrant. (B) Corresponding ultrasound showing parenchymal architectural distortion attributed to post-surgical changes. (C) Hematoxylin and eosin (H&E)-stained section of the excised specimen showing cribriform and trabecular growth patterns (×40). (D) H&E-stained section showing focal solid areas constituting 15%–20% of the tumor (×100). (E) H&E-stained section showing another field highlighting the biphasic cellular population (×200). (F) H&E-stained section demonstrating perineural invasion (×100).

Case 3

A 54-year-old woman presented with a right breast lump. Mammogram showed an opacity with partially obscured margins in the right breast upper outer quadrant (Fig. 3A). Corresponding to the opacity, ultrasound also showed an ovoid isoechoic lesion in the right breast 9 o’clock position, circle 2 zone B, measuring 12×14×16 mm with marginal vascularity, figure for which has not been included here. The lesion was classified as BI-RADS category 4. Core needle biopsy revealed adenoid cystic features with low mitotic activity (Fig. 3B-D). IHC was ER–, PR+ (weak, Allred 3/8), HER2–, Ki-67 15%–18%. PET-CT confirmed no metastasis. The patient was scheduled for surgical excision. The patient went ahead with the procedure at another center, where the diagnosis of AdCC (pT1c N0) was confirmed with c-KIT. No recurrence has been reported on follow-up.

Fig. 3.

Case 3. A 54-year-old woman with adenoid cystic carcinoma of the breast. (A) Mammogram showing an opacity with partially obscured margins in the right breast upper outer quadrant. (B) Hematoxylin and eosin (H&E) stained section from core needle biopsy showing classic adenoid cystic carcinoma features with low mitotic activity and characteristic cribriform architecture (×40). (C, D) H&E-stained sections showing the same field at higher magnification (×200) and (×400) respectively.

DISCUSSION

ACCB often presents as a palpable, solitary breast mass, with a minority of patients experiencing breast pain. Symptoms such as nipple inversion, nipple discharge, and skin retraction may also rarely occur. The disease typically exhibits slow, indolent growth, with an average diameter of 2–3 cm, although it can reach up to 15 cm [4].

Radiologically, the lesion is usually unifocal, with the retroareolar region being the most common site. ACCB lacks distinctive features. Mammography may show an irregular or well-defined round mass resembling benign lesions, complicating classification. Ultrasonography typically reveals an irregular hypoechoic mass with angular, indistinct, or microlobulated margins and mild peripheral blood flow. Contrast-enhanced magnetic resonance imaging offers high sensitivity for tumor size assessment and surgical planning [5].

Importantly, the 5th edition of the World Health Organization Classification of Breast Tumors delineates three histologic subtypes of AdCC with distinct clinicopathological profiles: (1) Classic AdCC, characterized by cribriform and tubular growth patterns and low-grade cytology, this subtype follows an indolent clinical course; (2) Solid-basaloid AdCC, which exhibits solid nests, nuclear atypia, and necrosis, and is associated with a higher risk of recurrence and metastasis; or (3) AdCC with high-grade transformation, a newly recognized, aggressive variant defined by an abrupt transition from classic AdCC to an undifferentiated carcinoma, featuring loss of the characteristic biphasic morphology and increased mitotic activity [6].

Ro et al. [7] initially categorized breast AdCC into three grades based on the presence of solid components within the lesion. Grade 1 indicates the absence of solid growth, while in grade 2 tumors solid growth accounts for less than 30% of the lesion. Grade 3 tumors, on the other hand, exhibit solid growth comprising more than 30% of the lesion [7]. This classification aligns with the widely accepted notion that a higher percentage of solid components correlates with a poorer prognosis. However, histological examination alone may not suffice for classification, and in the case of AdCC it is always evaluated immunohistochemically, which allows for confirmation of the diagnosis [8].

The differential diagnosis of ACCB depends primarily on its structural pattern. When tubular structures predominate, they need to be differentiated from adenomyoepitheliomas. When solid (basal like) structures predominate, they need to be differentiated from small cell carcinoma, solid papillary carcinoma, anaplastic carcinoma, and malignant lymphoma [9,10].

ACCB typically does not express ER, PR, or HER2. Unlike other triple-negative breast cancers, ACCB displays a unique immunophenotype. Glandular epithelial cells commonly express CK7, CK8, CK18, and CD117, whereas myoepithelial and basaloid cells typically express p63, S-100, CK5, CK6, CK14, and CK17 [4].

The presence of focal, weak hormone receptor expression in the third case highlights that, while ACCB is classically triple-negative, rare immunophenotypic variations can occur.

Immunohistochemical staining for markers such as c-KIT (CD117) and myoepithelial markers (p63 and smooth muscle actin) aids in confirming the diagnosis and excluding mimics. The luminal component shows strong CD117 positivity. Accurate diagnosis depends on correlating histological appearance with immunostaining results [11]. The second case in our series revealed classic adenoid cystic features (cribriform and trabecular patterns with focal solid areas) in the excision specimen, which alone were sufficient for diagnosis; therefore, c-KIT immunostaining was not repeated.

A study conducted in 2005 suggested that c-KIT immunoreactivity is the single most reliable diagnostic adjunct in differentiating AdCCs from infiltrating tubular and cribriform carcinomas: the overwhelming majority (95%) of AdCCs and none of the infiltrating tubular and cribriform carcinomas showed c-KIT expression in more than 10% of neoplastic cells [12].

Several studies employing proliferative markers such as Ki-67 have indicated a low proliferation rate in breast AdCC [8].

The majority of cases of AdCC of the breast harbor the MYB::NFIB fusion gene [t(6;9)(q22–23;p23–24)], which is considered a molecular hallmark of the diagnosis. The gene fusion can be detected by fluorescence in situ hybridization or polymerase chain reaction. In the absence of molecular testing, diffuse and strong MYB protein expression detected by IHC is often used as a surrogate, particularly in conventional AdCC [13]. We did not test for the fusion in any of our cases; however, it is considered a molecular hallmark of AdCC and may become a future therapeutic target. Elevated MYB protein expression on IHC further supports the diagnosis in many cases. Importantly, AdCC usually retains intact BRCA1 function and lacks the TP53 mutations typically seen in other triple-negative breast cancers [14].

Metastasis to axillary lymph nodes is exceedingly uncommon, though some patients may experience local recurrence or develop pulmonary metastases, sometimes occurring long after the initial diagnosis or treatment. Overall, the prognosis for this tumor group is generally favorable. The connection between microscopic grading and clinical outcome is still debated, with some studies suggesting that high grade or anaplastic-appearing tumors could follow a more aggressive course [11,15].

This case series adds to the existing literature by highlighting key diagnostic nuances in primary ACCB. Notably, we document an immunophenotypic variant with weak PR expression (Case 3) alongside a classic triple-negative profile, demonstrating that hormone receptor positivity—though uncommon—can occur and should not exclude ACCB from consideration. Additionally, we describe an atypical clinical presentation with Paget-like nipple changes (Case 2), a feature rarely emphasized in ACCB. These observations underscore that radiological and clinical mimics of benign lesions may delay diagnosis, and that strict adherence to the classic triple-negative immunoprofile risks misclassification. By illustrating this clinicopathological spectrum, the series reinforces the need for accurate recognition of ACCB to prevent misdiagnosis and overtreatment.

In conclusion, primary ACCB is a rare, triple-negative malignancy with an indolent clinical course and favorable prognosis. Diagnosis relies on recognizing its characteristic biphasic histopathology, supported by immunohistochemical markers such as c-KIT and myoepithelial markers. Accurate classification and distinction from histological mimics are essential to avoid misdiagnosis and overtreatment. Long-term follow-up is recommended due to the potential for late recurrence.