Unusual metastases to the breast from different extramammary malignancies: a multimodality imaging approach in a case series

Introduction

The majority of metastatic breast tumors, accounting for 98% of cases, originate from either ipsilateral or contralateral initial breast cancer. The predominant extramammary breast metastases, accounting for 2% of cases, are attributed to lymphoma, malignant melanoma, or pulmonary carcinoma. In contrast, carcinomas originating from the ovary, stomach, thyroid, cervix, and endometrial, as well as sarcomas and myelomas, exhibit lower incidence rates (1). Most the breast metastases present palpable, relatively well-circumscribed and freely movable masses, pain, tenderness, and inflammation. In up to 50% of cases, these lesions may be the first manifestation of the primary tumor (2). On mammography, breast metastases can be mistaken for benign tumors or primary breast malignancies. A comprehensive understanding of the many cancers capable of spreading to the breasts, along with precise diagnosis, is essential to prevent unwarranted mastectomy and to inform subsequent therapeutic interventions (3). In order to distinguish breast metastases from original breast cancer or benign breast lesions, a combination of imaging modalities is necessary due to the absence of dependable clinical and specific radiological indicators (2,4). This pictorial essay aims to review the main findings of metastatic lesions to the breast using different imaging methods, including mammography, ultrasound, computed tomography (CT) and positron emission tomography-CT (PET-CT). In addition, we present eight cases of breast metastases that are unusual cases, which makes them a valuable addition to the findings of the current literature.

Clinical examples

Breast metastases from endometrial adenocarcinoma (ECC)—report of two cases

ECC is the predominant gynecologic cancer among women in the Americas. It is projected that more than 60,000 new cases will be diagnosed during the upcoming year, resulting in around 11,000 fatalities. The highest rate of diagnosis occurs between the ages of 55 and 64, with a median age of 62 years (5,6). Individuals with high body mass indices (BMIs), type II diabetes, insulin resistance, anovulation, menstrual difficulties, amenorrhoea, and infertility are at an increased risk of developing both low-grade and high-grade endometrioid cancer (6). While American black women have a slightly lower risk of developing endometrial cancer compared to white women (24.8 versus 26.3 new cases/100,000 per year), the mortality rate is significantly higher in black women (8.1 versus 4.2 deaths/100,000 per year). One plausible rationale for the observed disparity might be attributed to a notably elevated prevalence of advanced uterine corpus tumors and aggressive endometrial cancer histotypes (7).

Regarding metastatic endometrial cancer, it is well documented that this often spreads to the pelvis, abdominal lymph nodes, peritoneum, and lungs (8). Though it has been observed, metastatic spread from primary uterine cancer to the breast is extremely rare (8,9). As far as we know, in the literature, our cases represent the fifth and sixth ECC metastasis from the uterus. From a clinical perspective, breast metastasis and primary breast tumors have a comparable appearance, characterized by a detectable, non-painful lump, while skin alterations such as peau d’orange, nipple retraction, and nipple discharge are few (8). Significantly, certain metastatic breast masses tend to proliferate fast and in close proximity to the skin, maybe as a result of lymphatic involvement. This can lead to the thickening of the skin and trabecular structures, which may be misinterpreted as inflammatory breast cancer, as was the case for our patient number 1. At breast imaging (mammography and ultrasound), the patient from case 1 (Figure 1) is the first well-documented case presenting a mass with microlobulated margins resembling breast cancer (Figure 1A). A prominent axillary lymph node with high density was also shown in mammography (Figure 1A,1B).

Figure 1 Case 1. Endometrioid adenocarcinoma. A 51-year-old woman was referred to our hospital for a diagnostic work-up for axillary lymphadenopathy on her left side. Findings: both MLO (A) and CC mammography views (B) depicted a high-density mass with microlobulated margins, which was associated with skin thickening (thick arrow) and trabecular thickening. A prominent axillary lymph node with high density was also revealed. Images from ultrasound revealed an irregular hypoechoic mass with non-parallel orientation and heterogeneous echogenicity (C). A staging PET-CT scan shows FDG hot uptake in the left breast (SUVmax =22), axillary node (SUVmax =18) (D,E), left adrenal gland (SUVmax =12), liver and uterine cervix (D). Techniques: (A,B) mammography projection in MLO and CC of the left breast (Fujifilm Amulet Innovality, Kanagawa, Japan; kVp 37; mA 85). (C) Longitudinal plane ultrasound (Aloka Alpha 7, Tokyo, Japan). (D,E) Coronal and axial PET-CT (Siemens Biograph, Erlangen, Germany; 9.9 mCi ¹⁸F-FDG; 42 minutes injection time; kVp 120; mA 87; slice thickness 2 mm; without contrast). MLO, mediolateral oblique; CC, craniocaudal; PET-CT, positron emission tomography-computed tomography; FDG, fludeoxyglucose; SUVmax, maximum standardized uptake value.

Moreover, an irregular hypoechoic mass with non-parallel orientation and heterogeneous echogenicity was revealed at ultrasound (Figure 1C). Though the patient in case 2 (Figure 2) did not show any lesion on mammography (Figure 2A), she presented, at sonography, two axillary lymph nodes with eccentric fatty hilum and symmetric cortical thickening (Figure 2B), which also indicates the lymphangitic spread of the disease similar to case 1. In contrast, other authors remark that breast metastases from ECC are more likely to reveal benign features, such as well-circumscribed, round masses at mammography (8-11). In the same line, round, hypoechoic lesions with uniform internal structure and few reactive changes in the tissue around are the main sonographic findings reported in the current literature (9-11). It is important to mention that both of our cases have PET-positive breast and axillary metastatic lesions (Figures 1D,1E,2C). As expected, in this case, hypermetabolic activity was seen in the cervix (Figure 1D) and endometrium (Figure 2D).

Figure 2 Case 2. Endometrioid adenocarcinoma. A 57-year-old woman was initially referred to our hospital when she felt a mass in her left axillae. Findings: no suspicious lesion was observed on mammography (A). Meanwhile, an ultrasound revealed two axillary lymph nodes with eccentric fatty hilum and symmetric cortical thickening. It is important to mention that the numbering on ultrasound images corresponds to the number of nodes affected. In this case, we observed two suspicious nodes (B). Images of PET-CT show left axillary lymph nodes with hypermetabolic activity (SUVmax =16) (C) as well as endometrium (SUVmax =24) (D). The suspicious axillary lymph nodes were biopsied by core needle biopsy. The histopathological report resulted in a poorly differentiated metastatic carcinoma. Thus, an immunohistochemical analysis was performed. The neoplastic cells demonstrated strong positivity with PAX8 (E). The staining pattern and similar morphology of the primary endometrial tumor and metastatic tumor supported the diagnosis of metastatic endometrial adenocarcinoma. Techniques: (A) mammography projection in MLO of bilateral breast (Hologic Selenia Dimensions, Danbury; USA; kVp 27; mA 84). (B) Ultrasound with color Doppler of the left axilla (Aloka Alpha 7). (C,D) Axial PET-CT (Siemens Biograph; 8.9 mCi ¹⁸F-FDG; 51 minutes of injection time; kVp 120; mA 87; slice thickness 2 mm; without contrast). (E) IHC PAX/8 positive. PET-CT, positron emission tomography-computed tomography; SUVmax, maximum standardized uptake value; MLO, mediolateral oblique; FDG, fludeoxyglucose; IHC, immunohistochemistry.

Finally, immunohistochemistry (IHC) analysis showed negative signs pointing to hormone receptors (case 1, images not shown), GATA binding protein 3 to DNA sequence (GATA3) (cases 1 and 2, images not shown), napsin A (case 2, images not shown), mammoglobin (case 2, images not shown), thyroid transcription factor-1 (TTF-1) (case 2, images not shown), and human epidermal growth factor receptor 2 (HER2) (images not shown), with markers indicating endometroid adenocarcinomas such as paired box gene 8 (PAX8) (case 1, images not shown, and Figure 2E), tumor suppressor protein p16 (images not shown), and cytokeratin 7 (CK7) (images not shown).

Breast metastasis from multiple myeloma (MM)

The haematological malignancy known as MM is characterised by the clonal proliferation of plasma cells in the bone marrow, accompanied by an elevated production of monoclonal immunoglobulins. The mean age of patients at diagnosis is often in their sixth decade of life, and the occurrence of the illness is exceedingly uncommon in people under the age of 40 (12). MM can affect extraosseous sites as solitary lesions (extramedullary plasmacytoma) or as a presentation of MM relapse in less than 5% of cases. Rare documentation of MM in the breast has been reported (12,13). The first case was documented by researchers in 1925. Since then, the literature has reported just 20 further individuals with breast involvement (13). Most patients with MM in the breast typically present with a palpable mass, although skin thickening and inflammation may occur and lead to confusion with breast abscess or inflammatory carcinoma at the clinical presentation. According to Ali et al. [2019], in a mammogram, MM can present as a single or multiple high-density round or oval lesion(s) that is/are circumscribed or ill-defined (14). At ultrasound, the imaging features that have been previously reported for this entity are well-defined, hypoechoic, or hyperechoic solid masses with hypervascularity (15). In the case presented here (Figure 3), the mammogram showed a high-density oval mass with an indistinct margin, favoring the diagnosis of primary breast carcinoma (Figure 3A,3B). There were no associated suspicious microcalcifications detected. A subsequent breast ultrasound revealed a mass with a cystic/solid composition, microlobulated margins, and parallel orientation. Both peripheral and penetrating vessels were also observed (Figure 3C). The low incidence and the lack of specific clinical and radiological characteristics make a preoperative diagnosis very difficult. In this context, it is important to mention that the breast lesion was incidentally found after a follow-up PET-CT scan (Figure 3D). Finally, IHC revealed that the cells were positive for cluster of differentiation 38 (CD138) as well as lambda-restricted, while their appearance was entirely consistent with a plasma cell neoplasm involving the breast.

Figure 3 Case 3. Multiple myeloma. A 51-year-old woman with multiple myeloma (IgG lambda). PET-CT scanning for staging showed two infiltrative hypermetabolic lesions, one of which was in the anterior mediastinum and the other one in the right breast. Findings: mammography showed a high-density oval mass with indistinct margin (A,B), while images from ultrasound revealed a mass with cystic/solid composition, microlobulated margins, and parallel orientation, which exhibited both peripheral and penetrating vessels at the color Doppler exam (C). PET-CT images after neoadjuvant chemoradiation therapy demonstrated a mass in the right breast (SUVmax =7) (D). Techniques: (A,B) mammography projection in MLO and CC of the right breast (Hologic Selenia Dimensions; kVp 31; mA 222). (C) Longitudinal and axial plane ultrasound with Doppler color (Aloka Alpha 7). (D) Axial PET-CT (Siemens Biograph; 9.2 mCi ¹⁸F-FDG; 41 minutes of injection time; kVp 120; mA 87; slice thickness 2 mm; without contrast). IgG, immunoglobulin; PET-CT, positron emission tomography-computed tomography; SUVmax, maximum standardized uptake value; MLO, mediolateral oblique; CC, craniocaudal; FDG, fludeoxyglucose .

Breast metastases from lung adenocarcinoma—report of two cases

The occurrence of lung cancer metastases to the breast is exceedingly uncommon, with an incidence rate ranging from 0.2% to 1.3%. In contrast, it has been shown that lung metastases are seen in 21–32% of breast cancer patients who have distant disease. Clinicians should take into account the potential diagnosis of metastatic lung cancer when discovering a breast nodule in patients of lung cancer (16). Nevertheless, it is worth noting that certain individuals may exhibit a breast nodule as the initial clinical indication of metastatic lung cancer, hence confusing the clinical evaluation of these patients (16,17). Here, we report two patients with breast metastases from pulmonary adenocarcinoma (Figures 4,5). The literature indicates that these patients usually present multiple, superficial, and well-circumscribed lesions at mammography (18-21). However, unusual manifestations have also been reported, such as masses with obscured margins (Figure 4A,4B), skin and trabecular thickening (Figures 4A,4B,5A,5B) and prominent axillary lymph nodes (Figures 4A,4B,5A,5B) (22,23). At ultrasound, the common features of breast metastases from lung cancer reported in the literature are irregular and hypoechoic nodules with microlobulated margins (16,22), as was in our case 4. A color blood flow signal was detected in this patient (Figure 4C).

Figure 4 Case 4. Lung adenocarcinoma moderately differentiated. A 43-year-old woman diagnosed with stage IV poorly differentiated lung adenocarcinoma. Six months after being diagnosed, she developed a palpable mass along with mastalgia in the left breast. Findings: Mammography projection in MLO (A) and CC (B) of bilateral breast mammography showing multiple masses with obscured margins and high density in the upper internal quadrant, which were accompanied by diffuse skin thickening (thin arrow). Lymph nodes (thick arrow) with round shapes and high density were also depicted. Ultrasound images displayed multiple irregular hypoechoic masses with microlobulated margins and vascularity (C). At CT, heterogeneously dense mammary parenchyma of the left breast was observed with multiple irregular nodules, which are ipsilateral to the lung lesion (D). Another finding was a loculated malignant pleural effusion (D). The immunohistochemical analyses exhibited positive cells for TTF-1, which corroborates the lung origin of the breast tumor (E). Techniques: (A,B) mammography projection in MLO and CC of bilateral breast (Hologic Selenia Dimensions; kVp 31; mA 84). (C) Ultrasound with color Doppler of the left breast (Aloka Alpha 7). (D) Computed tomography. (E) IHC TTF-1 positive. MLO, mediolateral oblique; CC, craniocaudal; CT, computed tomography; TTF-1, thyroid transcription factor-1; IHC, immunohistochemistry.

Figure 5 Case 5. Lung adenocarcinoma. A 34-year-old woman, the patient was referred to our hospital, presenting a palpable left breast lesion with ipsilateral chest discomfort. Findings: mammography projections in MLO (A) and CC (B) with asymmetry were detected in the left breast (thick arrow), with cutaneous and trabecular thickening. Non-mass lesions, as well as enlarged lymph nodes, were depicted at ultrasound (C). Disease extension was evaluated by using PET-CT (D). Images from this technique showed a large hypermetabolic intense FDG-avid ill-defined left breast lesion (SUVmax =19). Multiple hypermetabolic lung nodules (SUVmax =14.7) were observed. Techniques: (A,B) bilateral mammography projection in MLO and CC (Fujifilm Amulet Innovality; kVp 38; mA 321). (C) Ultrasound of the left breast (Aloka Alpha 7). (D) Axial PET-CT (Siemens Biograph; 9.7 mCi ¹⁸F-FDG; 40 minutes of injection time; kVp 120; mA 87; slice thickness 2 mm; without contrast). MLO, mediolateral oblique; CC, craniocaudal; PET-CT, positron emission tomography-computed tomography; FDG, fludeoxyglucose; SUVmax, maximum standardized uptake value.

Interestingly, we observed one patient with a diffused breast metastasis featuring posterior acoustic shadowing (Figure 5C), which, to our knowledge, is the first report resembling these features in breast metastases from lung adenocarcinoma. As mentioned earlier, both of our cases were accompanied by ipsilateral axillary lymphadenopathy. Prior research indicates that the dissemination of lymph from the mediastinal lymph nodes via the intercostal or supraclavicular lymphatic vessels might lead to the development of axillary lymph node metastasis and breast metastases on the same side. Additionally, lymphatic drainage from the chest wall may contribute to the situation. Enlarged axillary lymph nodes on the same side may provide evidence for these causes in the cases presented here (16,24). Thus, ipsilateral lung cancer, breast lesions, and axillary lymphadenopathy should raise one’s suspicion of a metastatic lung cancer process. Finally, in case 5, disease extension was evaluated by using PET-CT, in which was observed a breast hypermetabolic lesion as well as multiple ipsilateral hypermetabolic lung nodules (Figure 5D).

At IHC, our differential diagnosis included primary breast carcinoma and metastatic carcinoma from the lungs. The tumor cells demonstrated immunoreactivity for TTF-1 in both cases (Figures 4D,5; image not shown), as well as for napsin-A in case 5 (images not shown). Neither GATA-3 nor gross cystic disease fluid protein-15 (GCDFP-15) were expressed by the neoplastic cells in case 5 (images not shown), which was expected since both markers are used to exclude the mammary origin.

Breast metastasis from papillary thyroid cancer (PTC)

PTC constitutes approximately 80% of malignant thyroid tumours, with a higher prevalence of regional neck metastasis compared to distant metastasis. Toraih et al. [2021] reported that the lungs exhibit the highest prevalence of distant metastases, accounting for 53.4% of cases. This is followed by bone at 28.1%, liver at 8.3%, and brain at 4.7%. In contrast, metastases in other organs, including breasts, skin, eyes, pancreas, and skeletal muscle, are few. The presence of distant metastases greatly raises the mortality rate of PTC. Additionally, patients with multi-organ distant metastasis had a much shorter median survival time compared to those with single-organ distant metastasis, with a survival time of 6 months against 29 months, respectively (25,26). Diagnosis of thyroid metastasis is difficult, and in general, most cases are asymptomatic, but the appearance of solitary or multiple palpable masses has been reported (27). For example, Mandanas et al. reviewed 20 cases of thyroid cancer metastasizing to the breast in which 10 patients were asymptomatic and the other 10 showed palpable breast tumors (single or multiple and unilateral or bilateral) (28). Breast enlargement and mastalgia were the main clinical manifestations in our patient. As far as we know, there are no cases of breast metastases from thyroid carcinoma describing specific findings on imaging. In general, it is accepted that both mammography and sonography findings of these lesions are in line with other extramammary secondary lesions. For example, single or multiple high-density mass/masses; round, circumscribed, possibly micro-lobulated, or indistinct margins without a desmoplastic reaction are expected at mammography, while sonography might reveal round or oval mass/masses with circumscribed, indistinct, or micro-lobulated margins (2).

Interestingly, our case in Figure 6 exhibited, at mammography, skin thickening and enlarged lymph nodes in the axillary regions (Figure 6A,6B), which was corroborated by both PET-CT (Figure 6C) and ultrasound (Figure 6D). As we mentioned earlier, skin thickening, lymphedema and enlarged lymph nodes suggest a lymphatic dissemination of the disease. Thus, this spread route is suspected in the current patient. Histological and immunohistochemical evaluations confirmed breast metastasis from PTC. Particularly, we report the immunohistochemical expression of integrase interactor 1 (INI-1) (Figure 6E), which is usually maintained in all thyroid tissues (benign and malignant) (29).

Figure 6 Case 6. Papillary thyroid cancer. A 46-year-old woman with papillary thyroid cancer and unresectable mediastinal recurrence. Eight months after being diagnosed, she was referred to our service for enlargement of her left breast and mastalgia. Findings: MLO mammography view depicted round and enlarged lymph nodes in the left axilla (A). Skin thickening and trabecular thickening were also observed on the CC view (B). On an ultrasound exam, round lymph nodes were observed, some of which had diffuse cortical thickening, whereas others had a loss of the fatty hilum (C). PET-CT images demonstrated skin thickening of the left breast (SUVmax =2), as well as supracervical, mediastinal and axillary lymphadenopathies (SUVmax =15) (D). According to the immunohistochemical analysis, INI-1 diffuse nuclear was positive, which confirmed breast metastases from papillary thyroid cancer (E). Techniques: (A,B) mammography projection in MLO and CC of the left breast (Fujifilm Amulet Innovality; kVp 28; mA 74). (C) Ultrasound with color Doppler of the left axilla (Aloka Alpha 7). (D) Coronal PET-CT (Siemens Biograph; 10 mCi ¹⁸F-FDG; 49 minutes of injection time; kVp 120; mA 87; slice thickness 2 mm; without contrast). (E) IHC INI-1 positive. MLO, mediolateral oblique; CC, craniocaudal; PET-CT, positron emission tomography-computed tomography; SUVmax, maximum standardized uptake value; INI-1, integrase interactor 1; FDG, fludeoxyglucose; IHC, immunohistochemistry.

Breast metastasis from cervical cancer

Breast metastases originating from gynecologic malignancies exhibit a low incidence rate. Metastasis to the liver, lungs, and bones is the most prevalent occurrence of cervical cancer. In cases when cervical cancer infiltrates the breast, it often manifests as a single tumor in the breast, while, in rare instances, breast metastases may resemble inflammatory breast cancer (30). To our knowledge, this is the third case reported in the literature of metastatic cervical adenocarcinoma presented as an inflammatory breast cancer. In a previous study conducted by Ward et al. [1989], a case was presented involving a 48-year-old woman who had the abrupt development of swollen and painful right breast, accompanied by erythema and peau d’orange, roughly 18 months after being diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IIB. The results of a breast biopsy indicated the presence of adenocarcinoma, namely cancer antigen 125 (CA-125), a marker commonly associated with gynecologic adenocarcinomas (31). More recently, Cholmondeley et al. [2019] described the case of a 35-year-old patient experiencing erythema and fullness of the left breast, in which a CT scan, mammography and ultrasound identified asymmetric skin thickening and mildly prominent left axillary nodes. Immunohistological analysis of the axillary biopsy in the case reported by Cholmondeley et al. showed diffuse and intense reactivity for p16 and negative reactivity to mammoglobin, suggesting a cervical origin (30).

In the case presented here in Figure 7, mammography showed skin and trabecular thickening (Figure 7A). On ultrasound, multiple hypoechoic masses with microlobulated margins were seen in the parasternal region. Additionally, enlarged lymph nodes with fat necrosis were seen in the left axillae (images not shown). PET-CT images demonstrated subcutaneous lesions with increased fludeoxyglucose (FDG) uptake in the anterior chest wall (Figure 7C). Positive p16 (Figure 7D) and PAX8 reactivity, indicators of human papillomavirus (HPV)-related cancer, were used to sustenance the diagnosis of metastatic cervical cancer in the biopsied breast and axillary node tissues, while negative reactivity for GATA-3, cytokeratin 14 (CK14), tumor protein 63 (p63) helped to decrease the likelihood of a second primary breast cancer.

Figure 7 Case 7. Cervical cancer. A 65-year-old woman with stage IIB cervical cancer. One month after being diagnosed, she developed a palpable mass in the left breast. Findings: MLO mammography views showed skin thickening (thin arrow) and trabecular thickening (thick arrow) (A). On ultrasound, multiple hypoechoic masses with microlobulated margins were seen in the parasternal region. It is important to mention that the numbering on ultrasound images corresponds to the number of nodes affected. In this case, we observed two suspicious nodes (B). During the color Doppler exam, these masses showed enhanced vascularity. Additionally, enlarged lymph nodes with fat necrosis were seen in the left axilla. PET-CT images demonstrated subcutaneous lesions in the anterior chest wall (SUVmax =2) (C). Pathology reported a poorly differentiated metastatic tumor. According to the immunohistochemical analysis, the expression of GATA-3, CK14, p63 and chromogranin was negative, while PAX8 and p16 (D) confirmed breast metastases from cervical cancer. Techniques: (A) mammography projection in MLO of bilateral breast (Hologic Selenia Dimensions; kVp 24; mA 50). (B) Ultrasound of the left breast (Aloka Alpha 7). (C) Axial PET-CT (Siemens Biograph; 9.3 mCi ¹⁸F-FDG; 46 minutes of injection time; kVp 120; mA 87; slice thickness 2 mm; without contrast). (D) IHC p16 positive. MLO, mediolateral oblique; PET-CT, positron emission tomography-computed tomography; SUVmax, maximum standardized uptake value; FDG, fludeoxyglucose; IHC, immunohistochemistry.

Breast metastasis from alveolar soft part sarcoma (ASPS)

The ASPS is a highly uncommon tumour that often manifests in the lower extremities of individuals in the paediatric and teenage age groups. Upon definite diagnosis, 60–70% of patients have distant metastases to the lungs, bones, and brain. The prognosis for this illness is unfavourable, with an average survival period of around 40 months (32). According to available data, metastatic breast tumours account for around 0.5–2.0% of all malignant mammary neoplasms. Instances of ASPS accompanied by mammary metastases are exceedingly uncommon (32,33). To the best of our knowledge, there are only 10 previous studies of breast metastases from ASPS in women between 11 and 29 years old. Most of them were cases with a known primary tumor histologically verified as ASPS (34). Asano et al. reported that about half of the cases were multiple organ metastases (number of lesions: range, 1–3, median 1.5) (32).

Here, we report a case of a 23-year-old woman presenting a palpable breast mass about one month after her diagnosis of ASPS (Figure 8). Mammography was not performed because the patient was under 30 years old. However, ultrasonography shows irregular masses, suggesting a greater likelihood of malignancy (Figure 8A,8B). According to the literature, blood-borne metastasis to the breast typically manifests as one or more round, discrete nodules that cannot be differentiated from benign nodules from a purely radiologic standpoint, which makes findings from the present case uncommon (35). Additionally, lesions in case 8 were identified with high vascularity at the color Doppler images (Figure 8A,8B). Penetrating vessels that branch off in strange ways are usually linked with malignancy, although there is some similarity in the pattern and distribution of blood vessels between cancerous and noncancerous breast lesions (36). Finally, PET-CT images revealed hypermetabolic nodular lesions in the left breast and other regions (Figure 8C,8D), confirming the potential metastases. At IHC, positive expression of transcription factor E3 (TFE-3) was found, which is considered a pathological characteristic of ASPS (Figure 8E).

Figure 8 Alveolar soft tissue sarcoma. A 23-year-old woman with alveolar soft tissue sarcoma of the left foot. One month after being diagnosed, she was referred to our service by presenting two masses in her left breast. Findings: during the ultrasound examination, irregular masses were observed. One of them was microlobulated, while the other was circumscribed. Both nodules were parallel in orientation and heterogeneous. In addition, these lesions were identified with high vascularity in the color Doppler images (A,B). PET-CT images demonstrated nodular lesions in the left breast (SUVmax =3) (C). A metastatic hemi pelvic lesion affecting the abdominopelvic region as well as the groin area (SUVmax =6.4) was also seen in PET-CT images (D). According to the immunohistochemical analysis, the expression of TFE-3 was positive (E). Techniques: (A,B) ultrasound with power Doppler of the left breast (Aloka Alpha 7). (C,D) Axial PET-CT (Siemens Biograph; 9.1 mCi ¹⁸F-FDG; 41 minutes of injection time; kVp 120; mA 87; slice thickness 2 mm; without contrast). (E) IHC TFE-3. PET-CT, positron emission tomography-computed tomography; SUVmax, maximum standardized uptake value; TFE-3, transcription factor E3; FDG, fludeoxyglucose; IHC, immunohistochemistry.

Discussion

Extramammary malignancies refer to cancers that occur outside the breast tissue. These malignancies can arise in various tissues and organs, and their characteristics, treatment approaches, and prognoses can differ significantly from breast cancer (37). Metastasis to the breast from non-mammary malignancies is rare; it happens in less than 1% of all breast cancers (38). No clear risk factors are linked to the development of breast metastasis. Several mechanisms have been suggested to explain endocrine resistance, including the disruption of different components of the estrogen receptors (ERs) pathway, changes in cell cycle and cell survival signalling molecules, and the activation of escape pathways that offer tumors alternative stimuli for proliferation and survival (39-41).

The usual symptomatology reported for secondary breast metastases is multiple painless breast masses and pain or discomfort (42,43). Nipple abnormalities, discharge, skin involvement and axillary lymphadenopathy are believed to be infrequent (43). In the same line, systemic symptoms such as fever, night sweats, and weight loss are reportedly uncommon and occur only in 9% of cases (44). However, some authors indicate that this percentage can vary based on the primary cancer site and extent of metastatic involvement, suggesting that recognizing the signs and symptoms of breast metastases from extramammary malignancies is crucial for early detection and appropriate management (42-45).

In the radiological evaluation of breast lesions arising from different extramammary malignancies, a combination of imaging modalities to provide a comprehensive understanding of the lesion’s characteristics is mandatory (43,45-48). These modalities must comprise mammography and ultrasound, but also digital breast tomosynthesis (DBT), magnetic resonance imaging (MRI), and PET-CT if resources preclude access to these modalities (43,49). It is well recognized that the role of PET-CT is to evaluate the extent of disease local staging prior to therapy and assess post-treatment responses (49,50). The best thing about PET-CT is that it can show all of a person’s cancer by showing FDG activity in the breasts, axillae, and other places where the cancer has spread (46-47,50).

As it was previously described, on mammography, metastatic breast neoplasms usually show up as a well-defined mass that looks like a benign lesion. On the other hand, some metastases may have spiculated, microlobulated (case 1), or unclear margins (case 2), making them look like primary breast cancer. Mammographic findings can also include asymmetry (case 4) or changes in breast density. The manifestation of abnormal lymph nodes in the axillary region and skin thickening might also occur (as in our cases 1, 3, 5, and 6). On ultrasound, breast metastases often look like solid masses, with margins that are spiculated (cases 2 and 3), microlobulated (case 5), or even circumscribed (case 8). The echogenicity can be different, and the lumps could be hypoechoic (cases 1, 3, and 5), isoechoic, or hyperechoic compared to the breast tissue around them. Also, these lesions may have a heterogeneous echo pattern due to necrosis or areas of hemorrhage within the mass (case 1). Color Doppler imaging may reveal increased vascularity within the lesion, although this finding is not specific to metastases (cases 2, 3, and 5) (43,45,51).

As we can see, the mammographic and ultrasonographic appearance of breast metastases from different extramammary malignancies can vary, and they are not always distinctive. For this reason, using a lot of different imaging methods together with clinical and histopathological correlation is very important for making a correct diagnosis (35). When dealing with patients who have a history of extramammary cancers or who present in a way that is not typical, radiologists should always be very suspicious. For a full and accurate evaluation of breast lesions that look different on imaging, radiologists, oncologists, and pathologists must also work together (52).

It has been previously discussed by our research group that different imaging features of breast metastases are connected to how primary malignant tumors spread, either through the blood or the lymphatic system. Accordingly, hematogenous metastasized tumors, commonly found in head and neck diseases like thyroid cancer, frequently develop distinct masses under the skin or near the mammary gland’s parenchyma, where there is ample circulation of blood. Conversely, lymphatically metastasized tumors, commonly found in gastrointestinal and gynecological malignancies, have indistinct borders, thickening of the skin and trabecular structures, and involvement of lymph nodes (51-55). Some of our cases—those with lung cancer (cases 3 and 4), cervical cancer (case 5), thyroid cancer (case 6), and endometroid cancer (case 7)—show imaging signs of a lymphangitic spread. As far as we know, this is the first series showing a high number of cases indicating that cancer spreads to the lymph nodes via the lymphatic system, which could advise the need to contextualize the lymphangitic route as a rapid escape for tumor cells (Table S1). In this way, the research suggests that lymphatic and blood vessels facilitate the rapid spread of several substances generated by tumors, such as cytokines, chemokines, growth factors, matrix metalloproteinases, and circulating tumor DNA. These factors contribute to the dissemination of tumors. The formal demonstration of the method by which these factors reach circulation has not been established. However, unlike tumor cells with the ability to move freely, they are most likely to be carried by interstitial fluid and are not likely to move against the flow (56). However, more cases, especially another type of research, are needed before any conclusions can be drawn.

At pathology, all our cases had the same histological features as the original tumor. For example, thyroid cancer cases had nuclear groves and intranuclear inclusions. Therefore, histologically, it was possible to diagnose these cases as metastatic tumors with careful observation. Nevertheless, an efficient IHC for the identification of specific markers was performed and showed up in some of our patients. For instance, we demonstrated positive staining for TTF-1 in breast metastases from pulmonary cancer in case 3, which is a marker normally expressed in lung epithelial cells (57). Still, in cases 5 and 7, positive results for PAX-8/p16 and PAX-8/CK-7 were exhibited. As it was described in our findings, PAX8 is a transcription factor that is very important for the development of the Müllerian system, which is where the female reproductive tract begins (58). We also display invaluable images of INI-1 alterations in case 6 of thyroid cancer. Even though INI-1 changes are not usually linked to thyroid cancer or metastases, its expression would be expected to be positive in thyroid cancer metastases to the breast, just like it is in normal thyroid tissue (58,59). Finally, the breast metastases in case 8 (ASPS) go beyond this report because this is an extremely rare cancer and metastases to the breast are also very uncommon, with only a few cases reported. ASPS is a distinct subtype of soft tissue sarcoma characterized by its unique histological appearance and often harbors a specific genetic translocation involving the ASPSCR1-TFE-3 gene fusion, which results in the overexpression of the TFE-3 protein (59). Thus, as it was observed in case 8 if TFE-3 staining is positive in breast metastases, it suggests that the primary tumor, or one of the primary tumors, is an ASPS.

The treatment of breast cancer metastases from different extramammary malignancies involves a comprehensive and individualized approach, considering factors such as the primary cancer type, the extent of metastatic spread, and the patient’s overall health, but, in general, a combination of radiation therapy, chemotherapy, and surgery could be mandatory (43,45,53,55). Emerging treatments in metastatic breast cancer should be considered, such as antibody therapies, selective estrogen receptor degraders (SERDs), PI3 kinase inhibitors, AKT inhibitors and immunotherapy, in order to improve the survival time of this patients (40,60).

Conclusions

Breast cancer that has spread can show up as a single nodule, a group of nodules spread out in different places, or a mass that is not clearly defined. When the breast metastatic lesion is diffuse, the appearance is indistinguishable from that of inflammatory breast carcinoma. Small, uneven, poorly defined nodules that are found on the surface of the breast and calcified on mammography and ultrasonography are signs of primary breast cancer, especially in people who do not know what their primary cancer is. In any case, a breast-confirmatory biopsy is mandatory.

Despite being rare, the radiologist must be familiar with the possibility of metastatic breast disease as part of the differential diagnosis. In the era of evidence-based medicine, we require information to support medical practice. In rare or uncommon cases, such as breast metastases of extramammary origin, the source information is through clinical cases found in daily practice, which is why the cases published in this paper add new information to what has been previously reported.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-23-142/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-142/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All clinical procedures described in this study were performed in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was waived because of the retrospective nature of the study and the use of anonymous clinical data. However, the participants or their parents have verbally consented to the submission of this study to the journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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