Clinical manifestation
There have been reports on ACC in salivary glands, digestive tract, external auditory canal, skin, uterus, and breast cancer [5, 6]. It is reported that ACC mostly occurs in superior lateral quadrant or below areola of breast. Patients are mostly admitted to hospital with the chief complaint of palpable masses. In most cases, the mass is in solitary and cases of multiple masses are rarely reported [7]. Seven patients in this study were reported with single tumor, and all the tumors of five patients were located in superior lateral quadrant. In addition, SIMONA et al. recommend a combination of LOCalizer™ and Intraoperative Ultrasound for localization and surgery in patients with non-palpable breast masses. The dual technique provides not only accurate localization but also better oncology and cosmetic results. Importantly, it also gives effective treatment to patients with non-palpable breast lesions [8]. As reported, pain in the affected area is another characteristic symptom of this disease, accounting for about 14% of all patients. Kashiwagi et al. revealed that such pain was related to perineural infiltration of tumor cells and contraction of myoepithelial cells [9]. Interestingly, most patients felt no pain at the first time of seeing a doctor. In our study, only two patients complained of occasional pain. It was reported that the average diameter of such tumors was 2–3 cm, and the maximum diameter ever seen was 15 cm [10].
Imaging manifestation
There is no significant specificity in the imaging presentation of primary breast ACC based on imaging of previous cases. It has been reported that the X-ray appearance of breast ACC can be irregular and high-density mass with fuzzy edge, containing slightly low-density or lipoid density lesions, with less calcification. Ultrasound appearance of breast ACC is non-mass like lesion with high echo and no distribution along direction of catheters. Likewise, there are some valuable findings on MRI. Most lesions of breast ACC are clear. On T2WI, large breast ACC can show extensive internal septum of high and low signal, which can be enhanced in delayed phase [11, 12]. Therefore, Katrina et al. concluded that combination of multiple imaging examinations could increase diagnostic efficiency, despite final diagnosis still depended on pathology [13].
Pathological grading and features
Pathological grading
The pathological grading of ACC is disputed. According to the cell structure, tumors composed of tubular or cribriform structures alone are classified into histological grade I; those with solid component < 30% are classified into histological grade II and those with solid component ≥ 30% are classified into histological grade III. The higher the percentage of solid components, the worse the prognosis of the patients [14]. Foschini et al. put forward another new classification standard of breast ACC: Grade I is the classic type ACC with tubular and cribriform features, which possesses favorable prognosis, meaning rare recurrence or metastasis after surgical. Grade II corresponds to solid breast adenoid cystic carcinoma (SBACC) with basal like features. Axillary lymph node metastases and local recurrence in this type are common, but the prognosis seems to be well. Grade III corresponds to the area of ACC malignant transformation, which may lead to distant metastasis and death [15]. There is also another classification system: classic ACC is classified into low grade and solid adenoid cystic carcinoma with basal cell like features is classified into high grade [3]. In a word, although there are debates on the grading system of breast ACC, we insist that it is crucial to grade this tumor appropriately, in terms of its potential impact on clinical treatment.
Pathological features
Under the light microscope, three common configurations can be seen: cribriform, tubular-trabecular and solid (Fig. 1). These structures are often mixed, exhibiting cystic and glandular changes or solid lamellar arrangement. The tumor is mainly composed of three kinds of cells: glandular epithelium cells, basal like cells and myoepithelial cells. Moreover, we can observe squamous cell metaplasia and sebaceous cell differentiation.
Genetic alteration
MYB is the first discovered proto-oncogene located in 6q22-23, which has strong carcinogenic effect and is known to be expressed in a variety of malignant tumors. Nuclear factor IB (NFIB) is a member of the NFI family and serves as a protein coding gene located in 9p23-24. It plays an important role in cell proliferation, apoptosis and development. ACC repetitive translocation t (6; 9) (q22-23; p23-24) leads to the fusion of MYB and NFIB, which is the main molecular mechanism of the disease. A large number of studies have shown that the fusion of MYB and NFIB is closely related to the occurrence and development of breast ACC. This fusion gene has no correlation with the location of ACC, meaning it can be detected in both primary and metastatic lesions. While reports of this fusion gene in other disease are rare, signifying its high specificity in ACC. Some studies have revealed that high expression of MYB protein can be detected even with negative expression of the fusion gene. Based on these findings, it was speculated that MYB played a vital role in ACC while NFIB just assisted fusion of proteins [16, 17]. It has been reported that detection rate of MYB-NFIB fusion gene in breast ACC is discrepant, related to tumor treatment therapy and detection methods. Brill et al. found that detection rate of the fusion gene in frozen samples was higher than that in paraffin preserved samples [16]. Some studies have also shown that MYBs labeled by immunohistochemistry (IHC) has higher sensitivity and specificity than those labeled by fluorescence in situ hybridization (FISH) [18]. Wetterskog et al. reported a detection rate of 92.3% by FISH and 30.8% by Reverse Transcription-Polymerase Chain Reaction [19]. Therefore, selecting an appropriate detection method can improve the detection rate. MYB-NFIB fusion gene and MYB gene play a key role in the molecular pathogenesis of ACC and are expected to be therapeutic targets. We still face many unknown challenges along the way.
Differential diagnosis
About 50% of breast ACCs are misdiagnosed [1]. In order to avoid incorrect classification, it is necessary to use strict diagnostic criteria, and it is particularly important to get the exact pathological diagnosis before making the treatment plan systematically. Some other diseases that can be differentially diagnosed are as follows:
Collagen corpuscle disease
Collagen corpuscle disease is a kind of pathological change under the microscope. While ACC is an independent invasive disease with visible tumors. There are some similarities between these two diseases in morphology of the sieve corpuscles. Both of them have substances like basement membrane. While corpuscles of collagen corpuscle disease have characteristic filiform, radial and coil like shapes and those of ACC contain interstitial or mucinous components, lacking structural characteristics.
Invasive cribriform carcinoma
Similar to ACC, invasive cribriform carcinoma possesses an obvious cribriform structure. But its cribriform cell nest is more irregular. The cribriform lining cells of invasive cribriform carcinoma lack expression of basal like cells and myoepithelium. The wedge-shaped pores do not contain matrix components, but rather protein mucus secretions and necrotic tissue. There is no eosinophilic basement membrane like substances around the cell nest. And the expression of ER and PR is often positive while smooth muscle actin and P63 are usually negative.
Cribriform ductal carcinoma in situ
Cribriform ductal carcinoma in situ is intraductal. The tumor cells show the features of glandular epithelium. ER and PR are often diffusely positive in cribriform ductal carcinoma in situ while they are often negative in ACC. There are no basal like cells and myoepithelium in the glandular cavity. The contents in the lumen are different from those in the pseudo-lumen of ACC.
Adenoid invasive ductal carcinoma
Cellular pleomorphism and atypia are more pronounced in adenoid invasive ductal carcinoma. There are more prominent vesicular nucleus and more abundant cytoplasm compared with ACC. Also, the former lack myoepithelium and obvious extracellular mucus.
Treatment and prognosis
Surgical treatment
Surgery is now recognized as the primary treatment for breast ACC patients. However, due to the rarity of this pathological type, there is no clear guidence in the selection of detailed surgical method for this disease, resulting in differences in treatment. Ro et al. suggested that the operation method should be selected according to the ACC grade. Tumor lumpectomy should be used for grade I tumors, mastectomy should be used for grade II tumors, and mastectomy plus lymph node dissection should be used for grade III tumors [20]. Here, we will discuss the operation methods of classic breast ACC and SBACC separately.
For classic breast ACC, it has been reported that relapse occurred after local excision by a clinical study including 478 cases of breast ACC patients [21]. The treatment includes tumor lumpectomy plus adjuvant RT, tumor lumpectomy alone, mastectomy alone and mastectomy plus adjuvant RT. Through Kaplan–Meier analysis, patients receiving tumor lumpectomy plus adjuvant RT had better survival compared with other patients, indicating lumpectomy plus adjuvant RT can improve the survival and BCS is a reasonable choice for breast ACC patients [22].
The axillary lymph node metastasis of classic breast ACC is rare, generally 0–2%. Axillary lymph node dissection (ALND) is not necessary if there is no preoperative definite clinical evidence of axillary lymph node metastasis. Thompson et al. investigated 244 patients with confirmed breast ACC, discovering that patients with unknown lymph node status have the same favorable 10-year relative cumulative survival rate as known non-lymph node metastasis patients. Therefore, the author believed that ALND was not necessary for patients with breast ACC, especially for patients with T1 stage [23]. Kulkarni et al. designed a clinical study and included 933 patients with breast ACC, among whom 6% received axillary lymph node assessment and only 5% were axillary lymph node positive. He came to the same conclusion that ALND was not necessary for breast ACC patients [24]. However, when patients are with other tumors, or in the case of high-grade lesions, and diameter of breast tumor is larger than 3 cm, SLNB is a wise choice [3, 10]. At present, ALND is not recommended for classic breast ACC.
For SBACC, Shin et al. studied nine patients with SBACC and discovered that treatment of SBACC was different from that of traditional breast ACC. In six patients undergoing ALND, two of them were with axillary lymph node metastasis. Researchers have suggested that if there was no clinical evidence of obvious axillary lymph node metastasis, SLNB or low lymph node dissection should be carried out first. If axillary lymph node metastasis occurred, postoperative adjuvant CT would be non-avoidable. Therefore, SBACC is more invasive and has stronger axillary lymph node metastasis ability than classic ACC. And it seems to have a better prognosis than invasive ductal carcinoma in the same stage [25]. However, there are not immutable therapy regimens. Individual treatments according to specific circumstances of patients are the eternal truth.
Seroma formation
MRM is one of the common operations in breast surgery. Breast cancer patients who receive ALND have postoperative complications such as lymphedema, postoperative bleeding, seroma formation, skin paresthesia and upper limb dysfunction. Among them, seroma formation cannot be ignored, the incidence of 3%-85% [26]. Chronic seroma may lead to infection, overloading of the affected upper limbs, and lymphedema. In clinic, how to reduce the incidence of postoperative seroma has important clinical significance for improving the prognosis of breast cancer patients. Claudio et al. analyzed 100 patients with locally advanced breast cancer who underwent ALND and divided the patients into four groups according to the device utilized during the operation: Electrocautery, Harmonic Scalpel, LigaSure and Thunderbeat. The results found that the use of Thunderbeat could significantly reduce seroma formation, intraoperative blood loss and postoperative drainage. As you can see, the use of advanced hemostasis devices is highly advisable when performing ALND [27]. In addition, fibrin glue has also received attention in seroma formation. Giovanni et al. enrolled 30 elderly breast cancer patients who underwent ALND. Although they believed that fibrin glue could not prevent the formation of seroma, it could reduce the seroma extent, duration and length of hospital stay of the patients, thereby improving the prognosis of the patients [28]. Moreover, some clinical factors have been confirmed to be related to the seroma formation and can effectively reduce the occurrence of seroma, such as reduction of dead space [29, 30], suction drainage [31] and use of octreotide [32, 33]. Hypertension, diabetes mellitus and a high body mass index have been confirmed as risk factors for seroma formation by studies [34, 35]. Therefore, it is essential to identify high-risk groups for seroma formation in routine clinical work and take active preventive measures.
Adjuvant RT
There are literatures on postoperative adjuvant RT, showing that postoperative adjuvant RT can improve the overall survival (OS) and disease-specific survival of patients after receiving local surgery [36]. Khanfir et al. retrospectively analyzed 61 breast ACC patients undergoing BCS. The result indicated that 5-year local area control rate of patients with adjuvant RT was higher than those without RT. The author suggested that BCS should be the preferred treatment for patients with breast ACC and adjuvant RT could bring more benefits to patients [37].
Adjuvant CT
At present, there are still controversies about adjuvant CT after operation and no consensus is reached. Arpino G et al. suggested that postoperative adjuvant CT did not improve disease free survival or OS in breast cancer patients [3]. Treitl et al. investigated six patients with breast ACC, and none of them were found accompanied with lymph node metastasis. The researcher assumed that patients with breast ACC did not need adjuvant CT after operation [38]. Coincidentally, there is another study in which only 11.3% of all patients receive adjuvant CT after surgery [24]. However, for patients with axillary lymph node metastasis, some experts claim that systematic adjuvant CT is necessary and for patients with high-grade or large tumor with diameter larger than 3 cm, adjuvant CT should be considered [10]. In all, the relationship between postoperative adjuvant CT and prognosis of ACC patients needs to be further explored.
Adjuvant endocrine therapy
ACC of breast is often regarded as a subtype of TNBC. Therefore, endocrine therapy is unnecessary. Yigit retrospectively reviewed seven patients diagnosed with breast ACC. IHC showed that expression of progesterone receptor (PR) and HER2 was absent in all patients. Only one patient showed weak positive expression of estrogen receptor (ER). Besides, six of them showed positive expression of androgen receptor. Therefore, the author presented that hormone therapy could be applied in androgen receptor positive patients in the future [39]. However, more in-depth studies are needed to confirm this viewpoint. Vranic et al. tested IHC from eleven breast cancer patients and found that eight patients expressed ER-α36 while no patients expressed ER-α66, PR or HER2. This study indicated that ER-α36 was a novel subtype of ER-α66 and was overexpressed in breast ACC frequently [40]. ER-α36 may act as a new target for endocrine therapy in the future.