Teaching Case

A 45-year-old woman was diagnosed with FIGO stage IIIB mixed ovarian epithelial carcinoma. She underwent primary cytoreductive surgery, which was suboptimal due to the presence of multiple millimetric peritoneal implants, followed by adjuvant chemotherapy. Five months after the end of the treatment, she had a peritoneal progression. Two months later, she presented with an enlarged, painful, and diffusely erythematous left breast.

In the ovarian cancer diagnostic Contrast-Enhanced Computed Tomography (CECT), a mixed solid-cystic ovarian mass with associated ascitic fluid but no measurable peritoneal implants was found. (Fig. 1)

The patient underwent cytoreductive surgery in which millimetric peritoneal implants were seen, and therefore a complete resection was not possible. She received six cycles of adjuvant chemotherapy (Carboplatin AUC 5- Paclitaxel). Five months after the end of the treatment, a control CECT was performed, and peritoneal progression was diagnosed based on the presence of more ascitic fluid with positive cytology for malignant cells. (Fig. 2)

Two months later, coinciding with the date of her following control CECT, the patient presented left breast enlargement, diffuse swelling, and erythema (Fig. 3). The CECT performed that day showed asymmetric enhancement of the left breast and enlarged lymph axillary nodes in levels I, II, and III of the left side. (Fig. 4)

Given these findings further diagnostic workup of the breast was needed and DBT, US and MRI exams were performed. The DBT showed left breast skin thickening with an asymmetry at the upper quadrants of the left breast (Fig.5). In the US we did not find breast intraparenchymatous lesions underlying the asymmetry, we confirmed the skin thickening and also detected enlarged left axillary lymph nodes (Fig.6)

The MRI showed subcutaneous, breast and prepectoral oedema on the left side on T2 images. There was also an irregular heterogeneous, asymmetric non-mass enhancement in the left breast, which had a kinetic curve type 2. There were no defined masses. In addition, there were also enlarged left axillary lymph nodes. (Fig.7)

To obtain a final diagnosis the patient underwent an ultrasound-guided core biopsy of the axillary lymphadenopathies and a breast skin punch biopsy. The pathology report revealed metastatic disease from a known ovarian neoplasm (Fig 8).

Ovarian cancer often presents as a widespread disease. Nevertheless, it is confined within the abdomen in 85% of the patients [1].

Metastases to the breast are very infrequent and account for only 0.5% to 1.3% of breast malignancies. The most common extramammary sources of metastases to the breast are lymphomas and melanomas, as are carcinomas of the lung, stomach, or ovary [2, 3]. The most usual form of clinical presentation is a solitary tumour, while only 4% of the cases appear with a diffuse breast involvement [4].

On the one hand, compared to primary breast tumours, metastases usually present as well-circumscribed, dense masses. In the literature, it is reported that the location of breast metastases is often superficial (Klein, 2010).On mammography (MG), metastatic lesions appear as single or multiple non-calcified masses with circumscribed or ill-defined margins, and they typically lack spiculation or less frequently as diffuse skin thickening. On ultrasound (US), metastatic lesions tend to be hypoechogenic and have circumscribed margins occasionally with posterior acoustic enhancement.The colour Doppler US modality can help estimate the tumour’s vascularity, however, no specific pattern has been described for metastases. Persistent colour Doppler signal at the periphery of a breast lesion, also known as “positive rim sign”, has a sensitivity of 61% and specificity of 70% for malignancy, either primary or secondary [8].

The MRI findings may be indistinguishable from primary breast tumours, usually appearing as single or multiple masses with intermediate signal on T2 weighted sequences and low signal on T1 weighted sequences that show homogeneous contrast enhancement, with a plateau or washout kinetic curve (type II or III) on the delayed phase. They can infiltrate the skin, breast and thoracic wall. They may also show enlarged lymph nodes on MRI. [2, 5, 9]

On the other hand, the clinical signs and symptoms of Inflammatory Breast Cancer (IBC) are diffuse erythema, warmth, tenderness, oedema and diffuse induration involving at least one-third of the breast (‘peaud’orange,) and breast enlargement. The characteristic mammographic appearance of IBC is diffuse skin thickening; diffuse breast enlargement, global trabecular thickening and global asymmetry (diffusely increased parenchymal density). US findings include skin thickening and may also include solid masses and enlarged axillary lymph nodes. [5] Breast MRI is the most sensitive modality for the detection of disease local extent. Typical MRI findings of IBC include heterogeneous internal enhancement or extensive non-mass enhancement and diffuse skin thickening. Also, single or multiple masses with irregular margins may be foundin some cases[2, 5]. 

Diagnosis of IBC both in the clinical and the imaging setting may be challenging, especially in the absence of breast masses,because the characteristic disease features of diffusely increased density, stromal coarsening, and skin thickening resemble the inflammatory changes of mastitis, which is the principal differential diagnosis for IBC.  Both mastitis and IBC often manifests as cutaneous breast erythema and oedema with skin thickening and breast pain. There can be fever or other systemic inflammatory symptoms in mastitis, which might be helpful to differentiate both entities. If there is no response to antibiotic treatment within 1–2 weeks, malignancy such as IBC should be considered. [5, 6]

As we demonstrated in our case, clinical and radiological findings in patients with primary Inflammatory Breast Cancer and those with metastases to the breast may overlap. Therefore in patients with clinical and radiological findings consistent with Inflammatory Breast Cancer, who also have a history of a primary extramammary tumour, metastasis should be included in the differential diagnosis. [4]

Pathological findings and immunohistochemical study are the basis to differentiate metastases of ovarian cancer from a primary breast tumour.  However, both entities can yield similar results. There are some valuable markers such as PAX8 and GATA3, which were determined in our patient’s biopsy sample, resulting in PAX 8 positive and GATA 3 negative that helped the final diagnosis. PAX8 marker is positive in 87% of ovarian carcinomas and negative in all mammary carcinomas. GATA 3, on the other hand, is positive in 80-90% of primary and metastatic mammary carcinomas and negative in ovarian tumours. [7]

When metastases to the breast from ovarian cancer are diagnosed, it indicates a late-stage manifestation of the disease and the prognosis is significantly worsened. This entity should be treated as a systemic disease with specific chemotherapy treatment; however, the role of chemotherapy is limited as metastases from ovarian cancer to the breast have proven to have a high chemotherapy-resistance rate that has been reported to be due to specific aggressive clones. Surgery and radiotherapy are only offered palliatively. [1]

The patient of our case, after the diagnosis of breast metastases, started receiving Carboplatin and Doxorubicin based chemotherapy but unfortunately, that did not improve her prognosis, and she passed away just eight months later.

Future characterization of molecular and genetic markers will be essential to find new therapeutic targets that might help improve the prognosis of this disease. [1]