Case report
In March 2022, a 77-year-old female patient (Gravida, 22; Para, 12+10), was referred to the King Hussein Cancer Center (Amman, Jordan) complaining of a painless, gradually enlarging right breast mass associated with left nipple inversion and tenderness for a 6-month duration. Apart from this, the systemic review of symptoms did not yield any significant findings. The patient was known to have a history of hypertension, diabetes mellitus type II, osteoarthritis and chronic kidney disease. The surgical history included an open cholecystectomy and hysterectomy with bilateral salpingo-oopherectomy performed at the age of 57 years related to post-menopausal bleeding due to non-malignant causes. Menarche occurred at the age of 13 years, and the patient had been in menopause for the past 22 years. There was no family history of malignancies. The patient was a second-hand smoker with no hormonal replacement therapy usage. During physical examination, a mass measuring 4×5 cm was identified in the mid-upper quadrant area of the right breast, situated 5 cm away from the nipple areolar complex. The mass was mobile, without any concurrent skin alterations or retraction of the right nipple. Notably, palpable lymph nodes were observed in the ipsilateral axilla. Otherwise, examination of the left breast, left axilla and bilateral supraclavicular region revealed no notable findings.
A mammogram demonstrated an irregular spiculated hyperdense mass at the mid upper right breast ~9.5 cm away from the nipple (Fig. 1A). Subsequent breast ultrasound (U/S) imaging revealed an irregular, heterogeneous hypoechoic mass with indistinct margins at the mid upper right breast measuring 1.7×1.3×2 cm, with no concerning findings in the left breast (Fig. 1B). Lymph node involvement was notably absent in both axillae. Further staging computed tomography (CT) scans revealed an ill-defined soft-tissue lesion consistent with the previously identified right-sided breast mass (Fig. 1C). Bone scans were free of any active lesions, and there was no evidence of metastases to nearby or distant organs (Fig. 1D). Additionally, CT scans revealed prominent subpectoral and mediastinal lymph nodes on the ipsilateral side, measuring 0.8 cm and 1.2 cm, respectively (Fig. S1). A prior tru-cut biopsy performed outside our center revealed Nottingham histological grade I invasive ductal carcinoma and a ductal carcinoma in situ, characterized by a cribriform pattern with intermediate nuclear grade (13). Repeated diagnostic testing was performed to confirm the histological subtype and staging, to guide the multidisciplinary tumor board management plan.
In May 2022, the patient underwent a wide local excision along with additional excision of deep margins and a biopsy of the sentinel lymph nodes. The procedure was carried out successfully and there were no observed immediate or delayed post-operative complications. Subsequent surgical pathology reports revealed a 6.4-cm-diameter tumor composed of basaloid epithelial cells arranged in solid sheets, nests and tubules. Formalin-fixed, paraffin-embedded (FFPE) tissue specimens were prepared by fixing in 10% neutral buffered formalin for 24 h at room temperature, followed by paraffin embedding. Sections of 4-µm thickness were cut, placed in an oven at 60°C for 15 min, stained with H&E (hematoxylin for 8 min and eosin for 2 min at room temperature), and examined using a light microscope. In some areas, the tumor showed a lower grade component with evident myxoid stroma (Fig. 2A), whereas in other areas, the tumor showed a higher nuclear grade with numerous mitotic figures (Fig. 2B). The surgical margins were free of tumor with the closest margin being the superior margin at 0.3 cm. Perineural invasion was not observed. The tumor was positive for c-Kit (Fig. 2C), negative for S100 (Fig. S2) and tumor protein p63 (p63) (Fig. S3), and negative for chromogranin (Fig. S4), synaptophysin (Fig. S5), ER (Fig. S6) and HER2/neu (Fig. S7), immunostaining (procedure details described in Table SI). The solid areas represented >30% of the tumor. The diagnosis was consistent with solid-basaloid AdCC of the breast, Nottingham grade II (13). Ductal carcinoma in situ cribriform, intermediate grade was also observed. The tumor was staged as pT3N0, per the American Joint Committee on Cancer 8th edition staging system (14), indicating a large primary tumor size with no extension to adjacent viscera or nearby lymph nodes.
The case was discussed at the multidisciplinary tumor board meeting, and adjuvant radiation therapy was planned. At 1.5 months post-resection, upon evaluation at the Radiation Oncology Clinic at King Hussein Cancer Center for a CT simulation scan, a suspected lesion was detected in the axillary region, with a slightly atypical appearance (Fig. 3A). A U/S scan was requested, which revealed the presence of a new complex mass at the right axillary tail. Subsequently, a U/S-guided biopsy was performed, which confirmed the recurrence of known primary AdCC. Immunohistochemistry (IHC) analysis, carried out as aforementioned, of the axillary lesion revealed negative ER, weakly positive (2%) PR and negative HER2/neu expression, a proliferation index (Ki-67) of 50%, a limited number of cells staining positive for p63 and focal positivity for cytokeratin 8/18 (data not shown).
Given the unexpected findings, new staging work up was performed including bone scan revealed new multiple active lesions in the right iliac bone and ribs (Fig. 3B) and CT scan which shown significant disease progression manifested by new innumerable metastatic pulmonary nodules in both lungs, new liver metastases, new right axillary metastatic lymph nodes, new minimal right pleural effusion and thickening suggestive of metastatic deposits (Fig. 3C and D).
Prompted by the discovery of the new findings, the treatment plan included the initiation of chemotherapy sessions using weekly paclitaxel (144 mg) with a 20% dose reduction from the first cycle due to the age of the patient. The patient completed a total of three cycles. However, a multitude of complications occurred due to factors relating to the advanced age of the patient, comorbid conditions, side effects of chemotherapeutic agents and tumor infiltration. The patient presented to the Emergency Department on six occasions complaining of severe lower back pain, an episode of falling down and recurrent urinary tract infections. A CT scan revealed a non-displaced fracture in the right superior iliac crest and an inferior iliac crest fracture. Despite being on oral Tramal 100 mg twice daily, Tramal 50 mg every 8 h as needed, paracetamol 1,000 mg every 6 h, and gabapentin 300 mg three times daily, the patient continued to experience significant pain. Consequently, the patient required multiple admissions and palliative pain interventions, including haloperidol 1 mg IV every 4 h as needed, a continuous morphine sulfate infusion at 0.2 mg/h, and morphine 2 mg/2 ml IV every 2 h as needed for breakthrough pain. She also received multiple courses of intravenous antibiotics, with the most recent being meropenem 1 g diluted in 100 ml of 0.9% sodium chloride, infused over 30 min every 8 h. Unfortunately, chemotherapy sessions were postponed and subsequently discontinued due to a worsening clinical condition until stabilization was achieved. Over a span of 2 months, the patient suffered from neurological symptoms, manifesting as a decreased level of consciousness and seizures. Subsequent brain magnetic resonance imaging findings confirmed the presence of small bilateral hemispheric lesions suggestive of metastatic deposits (Fig. 4A and B). Concurrently, the urinary tract infections of the patient exhibited resistance to treatment. A final CT scan performed before clinical deterioration revealed no local recurrence of the right-sided breast cancer, with a partial response of the right axillary lymph node, a mild increase in right-sided pleural effusion and a new large lytic bone metastasis in the right iliac bone, with a non-displaced fracture of the right pubic bone (Fig. S8).
At 7 months after the initial diagnosis, the patient presented with a decreased level of consciousness. Clinical and diagnostic evaluation detected urosepsis, concomitant aspiration pneumonia and an acute-on-chronic kidney disease, with resultant metabolic acidosis and poor Glasgow Coma Scale (6/15) (15). After discussion with the family, the code status of the patient was changed to ‘do not resuscitate’ and the patient was administered comfort measures until they passed away 2 weeks later. The patient timeline of events is summarized in Fig. 5.
Discussion
It is considered that AdCC was first described as a ‘tumeur heteradenique’ by Robin and Laboulbene in 1853 (16). Subsequently, it was referred to as a ‘cylindroma’ due to the presence of cylindrical-shaped cells in a hyaline stroma (17). In 1953, the term AdCC was introduced by Foote and Frazell (18) to describe a distinct category primarily arising in the minor salivary, parotid and submandibular glands, comprising 3–5% of head and neck malignancies (18,19). AdCC also manifests as a rare subtype of primary breast carcinomas, which was first described by Geschickter and Copeland (20) in 1945. AdCC accounts for <0.1% of all breast cancer cases and 0.058% of total AdCC cases (7,9,21).
In a comprehensive cohort covering a 30-year interval, the age-adjusted incidence ratio was calculated to be 0.92 per 1 million person-years, predominantly affecting the female population, with a median age of onset falling between 50 and 60 years (11). Jang et al (22) reported lower overall survival (OS) rates in head and neck AdCC cases in age groups >70 years old compared with those in groups <45 years old. Zhang et al (23) supported the aforementioned association; however, conflicting opinions exist, with studies indicating lower OS in both age extremes (<45 and >60 years) (24,25). Notably, the age of the patient in the present study at symptom onset exceeded the average age documented in the aforementioned reports (24,25).
The clinical presentation and imaging findings of breast AdCC are non-specific, typically manifesting as a well-circumscribed, palpable mass, with no predilection for the left or right breast or specific quadrants (23). However, some studies have demonstrated a preference for the submastoid and upper outer quadrant region, while others have shown a 50% tendency for the subareolar region (10,23,26,27). Pain and tenderness upon palpation may be present, possibly due to the perineural invasion of the lesion (28). In the present case, the latter findings were not observed, as the histological assessment of the resected mass revealed no evidence of perineural invasion. The tumor usually ranges in size between 2 and 3 cm and exhibits a slow growth pattern (29,30).
Imaging modalities are able to detect AdCC; however, the efficacy of mammography in accurately distinguishing AdCC from its benign differentials remains uncertain. Typically, AdCC manifests as irregular masses with spiculated margins (7,31,32). In the present case, mammography revealed an irregular spiculated hyperdense mass, with a prior biopsy-proven confirmation of malignancy. Breast U/S and staging CT scans supported these findings; however, it is important to note the role that the post-resection CT simulation scan played in the early detection of recurrence. In the present case, CT simulation imaging was able to detect a suspected atypical lesion in the axillary tail at 1.5 months post-resection, aligning with existing studies of the paramount diagnostic value of the imaging technique in detecting new lesions and planning therapeutic strategies (33–35).
Histologically, AdCC diagnosis relies on identifying a dual cell population of myoepithelial and epithelial cells, presenting true duct-like structures with microvilli-projecting epithelial cells and pseudo-cyst structures lined by myoepithelial cells (11,36,37). AdCC is categorized according to the predominant growth structure into one or a combination of three groups, namely, cribriform, tubular and solid, with histological subdivisions holding prognostic value (38). Ro et al (39) proposed a classification for breast AdCC. Grade I is characterized by the absence of solid components, grade II exhibits <30% solid components and grade III exhibits >30% solid components. The 2019 World Health Organization classification of Tumors of the Breast highlights that the classic form of AdCC with predominant cribriform and tubular differentiation is more prognostically favorable, and such cases are recommended to undergo conservative treatment, in contrast to solid-basaloid AdCC and high-grade AdCC, which exhibit elevated rates of both local and distant recurrence (40,41). A comprehensive analysis by Slodkowska et al (42) involving 108 AdCC cases revealed a significantly higher incidence of distant metastasis in basaloid AdCC compared with that in classic AdCC (40 vs. 8%; P<0.0004). In a study by Marco et al (43), high-grade transformation of AdCC presented with skin and lung involvement in one patient, and lung, colon and brain involvement in a second patient, both of whom eventually died of disease. Examination of previously published case reports with distant metastases (Table I) (9,24,27,39,44–59), reveals a prevailing incidence of solid-basaloid AdCC and high-grade AdCC.
Following the American Joint Committee on Cancer guidelines (60), the utilization of the Nottingham score was endorsed in the present study, where scores exceeding 5 represent a higher grade and poorer outcome. The present case had a total score of 6/9 (tubular differentiation, 2/3; nuclear pleomorphism, 2/3; and mitotic activity, 2/3) (13). Despite the favorable score, the observed tumor size was 6.4 cm, surpassing the median size reported in prior studies (7,61). This notable size difference may have contributed as a factor to the subsequent aggressive behavior of the tumor in the patient, despite absence of initial extension to adjacent structures or lymph nodes (30). Factors affecting prognosis in AdCC of the breast include a solid growth pattern (>30%), basaloid morphology, lymphovascular invasion, perineural invasion, necrosis, lymph node involvement, positive margins and high Nottingham grade (12,40). In the present case, a few factors may have contributed to the worse prognosis, including the presence of significant solid and basaloid components, the large tumor size and the higher tumor grade, along with the increased mitotic activity and Ki-67 value, which eventually resulted in distant generalized metastasis.
IHC, genomic investigations and the distinct polarity of cellular structures are pivotal in achieving an accurate diagnosis of AdCC. This arises from the inherent challenge in distinguishing the solid-basaloid variant of AdCC from the more aggressive triple-negative breast cancer (TNBC) with basal-like features, where both entities share characteristics in terms of negativity for ER, PR and HER2/neu receptors. Additionally, they exhibit reactivity for basal high molecular weight CKs, including CK5/6, CK14, CK17 and luminal progenitors CK8/18 (62). Specifically, the luminal cells in AdCC exhibit positivity for CK7, CK8/18, epithelial membrane antigen and c-KIT, while myoepithelial cells exhibit positivity for CK5, CK5/6, CK14, CK17, p63, actin, calponin, S100, vimentin and epidermal growth factor receptor (63,64). A key difference between TNBC and AdCC lies in the loss of myoepithelium, and the loss of reactivity to p63 and calponin in TNBC (24). In the present case, IHC analysis of the recurrent lesion revealed triple-negative expression for ER, PR and HER2/neu, limited positivity for p63 and focal positivity for CK8/18. Notably, the Ki-67 value was markedly elevated at 50%, which is uncharacteristic of the proliferative activity associated with low-grade AdCC. Wetterskog et al (65) reported a low Ki-67 index in 69% of AdCC cases, with a moderate index in the remaining cases (66). This observation is particularly important, as Ki-67 has been established as a valuable marker of cellular proliferation, with higher levels being associated with increased tumor aggressiveness and poor clinical outcomes (67). High Ki-67 expression was associated with advanced histological grade and recurrence in a retrospective study (68). Another study found that Ki-67 immunoreactivity increased proportionally with tumor grade, averaging 27.12% in grade I, 34.43% in grade II and 38.45% in grade III tumors (69).
The majority of cases of AdCC of the breast harbor the transcriptional activator Myb:: nuclear factor IB (MYB::NFIB) fusion gene [t(6;9)(q22-23;p23-24)], which is considered a molecular hallmark of the diagnosis (48). The gene fusion can be detected by fluorescence in situ hybridization (FISH) or PCR (65,70). 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. However, this surrogate is less reliable for solid variants. Massé et al (71) reported that only 19% of solid-type AdCCs exhibited MYB gene rearrangements based on FISH, suggesting that this variant may be a distinct molecular entity enriched for CREB-binding protein and neurogenic locus notch homolog protein pathway mutations. We acknowledge the absence of MYB::NFIB testing in the present case due to institutional limitations. This represents a diagnostic limitation, as molecular confirmation would have further strengthened the diagnosis in the present study, particularly given the aggressive clinical course and high-grade histological features.
Breast AdCC is renowned for its indolent nature and favorable prognosis, distinguishing itself from its salivary gland counterpart and other forms of TNBC (54). Axillary lymph node involvement is rare, with Arpino et al (72) documenting lymph node metastasis in only 1 of 23 cases studied. Distant metastasis is also uncommon, following a hematogenous route and silent progression, and often emerging several years after the initial presentation. The lung is the most frequently affected organ, along with the occasional involvement of the liver, bones and brain (73). Consequently, various reports have argued against routine axillary lymph node dissection during surgery and underscored the importance of prolonged follow-up during remission (47,74,75). In the present study, to the best of our knowledge, all the previously reported cases of breast AdCC with confirmed recurrence and distant metastasis have been compiled and presented in Table I (9,24,27,39,44–59). The present case, alongside the case reported by Sołek et al (46) represent, to the best of our knowledge, the only two reported instances in the literature where the interval between resection and the detection of the first metastatic lesion was <3 months. While Sołek et al (46) exclusively reported lung involvement, the present case reported a broad spectrum of metastases, including those of the lungs, pleura, liver, bones and brain, culminating in a fatal outcome. Additionally, the discussed case is among the limited reports revealing axillary lymph node involvement, joining the case reports by Silva et al (49) Verani and Van der Bel-Kahn (56), Wilson and Spell (76), and Ro et al (39) in mentioning this uncommon manifestation.
Management strategies for AdCC of the breast vary across different clinical recommendations, particularly concerning the adoption of an aggressive surgical approach despite the recognized indolent nature of the tumor (77). Ro et al (39) proposed a treatment strategy involving local excision for grade I tumors, simple mastectomy for grade II tumors and mastectomy with axillary lymph node dissection for grade III tumors. Hodgson et al (78) suggested a more comprehensive approach due to the reported instances of positive margins post-excision, irrespective of the year of surgery or local practice patterns, but perhaps due to the silent and microscopic infiltration of the tumor into breast tissue. This mechanism may have contributed to the outcome of the present patient, as the treatment plan involved a wide local excision surgery coupled with radiotherapy sessions, which were halted by the discovery of local and distant recurrence of the disease, and then the commencing of chemotherapy. There is a consensus on the efficacy of lumpectomy or mastectomy with adjuvant radiotherapy in achieving remission and preventing recurrence, with no significant impact of adjuvant chemotherapy on OS (11,51,79,80). This was supported by a retrospective study of 488 AdCC cases conducted by Gomez-Seoane et al (81), which demonstrated an increased OS rate in the post-resection adjuvant radiation therapy group compared with that in those subjected to surgery alone.
National Comprehensive Cancer Network guidelines consider AdCC a favorable histology and only recommend adjuvant chemotherapy for pathological node positive disease (82). Furthermore, limited responses to neoadjuvant chemotherapy have been documented in solid-basaloid variants, with a complete pathological response remaining rare (83). However, evolving evidence has raised the need to reconsider whether adjuvant chemotherapy should be added for high-risk subtypes, particularly solid-basaloid and high-grade AdCC. Such variants have shown to be associated with more aggressive clinical behavior, higher rates of nodal involvement and early distant metastasis (42).
There are several potential limitations to the present study. First, its retrospective design may introduce bias and limit the ability to establish causal relationships. Second, the advanced age of the patient and their comorbidities presented significant challenges in administering various therapeutic options. Additionally, despite early surgical intervention, the aggressive nature of the solid-basaloid subtype of AdCC resulted in rapid metastasis and disease progression, underscoring the limitations of current treatment strategies in managing high-risk cases. In addition, the suitability of this tumor to represent a high-grade metaplastic, triple-negative, matrix-producing carcinoma is high. The case was subject to intradepartmental discussion and a consensus diagnosis was made based on the available histology, hormonal studies, immunohistochemical stains and clinical presentation at the time of first diagnosis. The gold standard for diagnosis is detecting MYB::NFIB gene fusion by molecular methods or detecting upregulation of MYB expression by IHC; however, neither tests were available at King Hussein Cancer Center. In summary, despite its indolent nature, certain subtypes of AdCC of the breast carry aggressive behavior manifested by short-term locoregional and systemic spread. The present report highlights the importance of a further understanding of AdCC of the breast, and the challenges that can arise in achieving control of this pathology.