Rare breast cancers with seemingly benign features on conventional imaging: Radio-pathological correlation and review of literature
How to cite this article: Sudhir R, Kodandapani S. Rare breast cancers with seemingly benign features on conventional imaging: Radio-pathological correlation and review of literature. Indian J Breast Imaging 2023;1:36-47.
Oval or rounded breast masses with circumscribed margins, absence of microcalcifications, and architectural distortions are usually benign. However, 10-20% of breast cancers may have circumscribed margins, which may be misdiagnosed as benign breast mass or lead to delayed diagnosis in advanced stages of cancer. Most frequently, circumscribed breast cancers are high-grade invasive ductal carcinoma of triple-negative molecular subtype. However, there are many other rare histological subtypes of cancers in the breast with circumscribed margins or less aggressive features on imaging and mimic benign breast lesions. A radiologist needs to be familiar with the imaging features of various atypical malignant breast tumors to avoid delay in diagnosis. These rare malignant breast tumors are mucinous carcinoma, papillary carcinoma, lymphoma, leukemia, myeloma, metastasis from extramammary primaries, adenoid cystic carcinoma, signet-ring carcinoma, malignant phyllodes tumor, mesenchymal sarcoma, Ewing’s sarcoma, and medullary carcinoma. This pictorial review illustrates the clinical, multimodality imaging features of rare malignant breast tumors with less aggressive features on conventional breast imaging with pathological correlation.
Rare breast cancers
rounded breast cancers
breast cancer with circumscribed margins
breast cancer imaging
radio-pathological correlation of rare breast cancer
A well-circumscribed breast lump without microcalcifications and architectural distortion is primarily benign. However, a small percentage (10-20%) of patients can be malignant and mostly high-grade infiltrating ductal carcinoma of triple-negative (estrogen, progesterone, and HER-2/neu receptors negative) molecular subtypes. Many breast cancers with rare histological diagnosis may also present with circumscribed smooth margins, which could be mistaken as benign breast lesions, leading to delayed breast cancer diagnosis and adversely affecting the prognostic outcome. A radiologist needs to be familiar with imaging features of various atypical malignant breast tumors to avoid delay in diagnosis. This article describes and discuss twelve cases of circumscribed malignant breast tumors with rare histological diagnoses.
Mucinous or colloid carcinoma
Mucinous carcinoma is a rare type of primary breast cancer that accounts for about 2% of all invasive breast cancers, commonly seen in older women and considered to have a better prognosis with a 10-year survival of 87-90.4%. It usually displays benign clinical and imaging features, leading to delayed diagnosis. On a mammogram, mucinous carcinomas are oval or rounded low-density or isodense masses with circumscribed or microlobulated margins. Calcifications are rare. On ultrasound, they are typically isoechoic or hyperechoic to the subcutaneous fat with posterior acoustic enhancement or no changes. On color doppler, they are usually hypervascular. Magnetic resonance imaging (MRI) shows variable signal intensity on T1-weighted images, the homogeneously or heterogeneously hyperintense signal on T2-weighted images due to rich mucin content, and heterogeneous or rim enhancement on post-contrast T1-weighted images. Histologically, they demonstrate small clusters of malignant cells floating in the mucin pool [Figure 1].
Solid papillary carcinoma
Papillary carcinoma accounts for less than 2% of all breast cancers, and solid papillary carcinomas are an even more uncommon entity, more frequently detected in postmenopausal women (>50 years of age). Patients usually present with bloody nipple discharge or a palpable central breast lump. On mammography, solid papillary carcinomas are usually rounded hyperdense masses with circumscribed margins and more commonly located in the retroareolar region. Calcifications within the mass may be seen in 25% of cases. Ultrasound with color doppler is the most sensitive imaging technique, which shows hypoechoic solid mass within a dilated duct, complex intracystic solid mass, or a homogeneous hypoechoic rounded solid mass with a large feeding artery [Figure 2]. On MRI, they appear as enhancing solid mass or complex cysts with enhancing mural nodules. Papillary carcinomas are usually slow-growing tumors and have a favorable prognosis. Solid papillary carcinomas are pathologically characterized by circumscribed rounded nodules composed of low-grade ductal cells separated fibrovascular cores and usually positive for estrogen and progesterone receptors, low proliferation index (ki-67 index), and negative for HER-2/neu. Additionally, they may be positive for neuroendocrine markers such as synaptophysin and chromogranin.
Breast lymphoma is an exceedingly uncommon entity, accounting for only 0.04-0.7% of all breast cancers. It is almost always of Non-Hodgkin’s (NHL) type. Breast lymphoma can be either primary or secondary lymphomatous infiltration of breast tissue. Primary breast lymphoma accounts for 0.85-2.2% of all extra-nodal lymphoma; the patients usually present with rapidly growing palpable breast lumps. Pain may be associated in 25% and axillary lymphadenopathy in 20-40% of patients. Primary breast lymphoma usually presents on mammography as a solitary, circumscribed, rounded, or oval hyperdense mass without calcification or architectural distortion. In the US, a homogeneous hypoechoic mass with distinct smooth margins is found [Figure 3]. Mass usually shows rapid initial enhancement and plateau or wash out in the delayed phase (Type II or III kinetic curve) on contrast-enhanced dynamic MRI. On histological examination, diffuse large B cell lymphoma is the most typical type of NHL detected, followed by follicular lymphoma. Similar to other lymphomatous locations, breast lymphoma does not require surgical excision, and chemotherapy is the preferred therapeutic option. The prognosis depends on the stage and histological subtype of breast lymphoma.
Breast involvement due to leukemia is rare, with less than 200 cases reported. Leukemic involvement of the breast can be seen either as an isolated lesion or as a part of systemic disease or as a relapse. Clinically, most cases of breast leukemia usually present as rapidly enlarging, painless, palpable breast lump. Lumps may be bilateral or multiple simulating fibroadenomas. Axillary lymphadenopathy may be seen in 17% of cases. Mammographically, breast leukemias are commonly identified as rounded or oval iso or high-density mass with circumscribed margins. Microcalcifications are exceedingly rare. On ultrasound with color Doppler, they show single or multiple hypoechoic or heteroechoic masses with circumscribed or microlobulated margins, posterior acoustic enhancement and intralesional vascular flow [Figure 4]. On contrast-enhanced MRI, breast leukemia lesions show intense rapid enhancement with washout (Type III kinetic curve). Ninety percent of breast leukemias are T-cell neoplasms; the remaining 10% are B-cell neoplasms. Aspiration biopsy shows blast cells with hyperchromatic nuclei and scanty cytoplasm. The immunohistochemistry (IHC) profile shows positivity for CD19, CD 79a, and CD 22 and variable expression for CD20, CD 34, CD45, and CD 99.
Similar to other hematological malignancies, myeloma of the breast is also rare. It may present as primary breast myeloma (plasmacytoma) or as a part of the extramedullary manifestation of disseminated multiple myeloma. Primary breast plasmacytoma is exceedingly rare (0.01%), and about 20% may develop multiple myeloma later in life. Bone marrow biopsy is required to confirm or rule out disseminated multiple myeloma. On mammography, they appear as single or multiple hyperdense masses with circumscribed margins in 50% of cases and without microcalcifications. They are most frequently present on ultrasound as rounded hypoechoic circumscribed masses with posterior acoustic enhancement, intralesional vascular flow, and axillary lymphadenopathy [Figure 5]. The histological hallmark of plasmacytoma is the presence of several atypical plasma cells with irregular nuclei, prominent nucleoli, and scanty marrow plasma cells (<5% of the marrow cells). IHC shows diffuse positivity for the CD138 marker, and 50% of plasmacytomas may express CD31.
Breast metastases from extramammary primary are rare, with an incidence rate of 1.3% to 2.7%. The common primary malignancies that can metastasise to the breast are melanoma, lung, ovarian, and renal carcinomas. Clinically, they present with unilateral palpable painless breast lump, commonly located in the upper outer quadrant. On mammography, breast metastases from the extramedullary primary are usually single (85%), rounded or oval, isodense or high density masses with circumscribed margins without architectural distortion and calcifications. On ultrasound, hypoechoic or mixed echogenic rounded or oval mass with posterior acoustic enhancement [Figure 6]. Axillary lymphadenopathy is unusual. Histological diagnosis of breast metastases is more difficult in an occult extramammary primary malignancy. However, the clinical details and specific immunohistochemical markers may help in the differentiation of primary breast cancer (hormone receptor, gross cystic fluid protein-15, and CK 7 positive) and metastases from extra-mammary primary (e.g., S100, HMB-45, melan-A for melanoma).
Adenoid cystic carcinoma
Adenoid cystic carcinoma (ACC) of the breast is rare, with an incidence of less than 0.1-0.4% of all breast cancers. Unlike ACC of the salivary gland, ACC of the breast is usually a low-grade tumor and has a very good prognosis with low recurrence rate. Axillary node metastases are rare. Mammographically, ACCs have been described as either focal or developing asymmetric densities or iso to hyperdense mass with circumscribed margins without associated calcifications. On ultrasound, they are hypoechoic or heteroechoic, oval or rounded masses with circumscribed margins. On color Doppler, peripheral vascular flow may be appreciated. On MRI, mass shows variable signal intensities on T1 and T2-weighted images and rapid heterogeneous enhancement with washout on dynamic post-contrast imaging. Histopathology shows an adenoid cystic pattern with large and small cribriform mucinous tumor nests around the tumor stroma [Figure 7].
Signet ring cell carcinoma
Signet ring cell carcinoma (SRCC) is a mucin-producing adenocarcinoma, which can be seen originating from the stomach, colon, lung, breast, and prostate. SRCC of the breast is rare, with incidence ranging between 2% and 4.5%. It can be either primary breast SRCC or metastasis from extramammary SRCC, which can be differentiated based on immunohistochemical markers. Primary breast SRCC is rare, reported as isolated cases or small case series. Like extramammary SRCCs, breast SRCCs are aggressive tumors that frequently metastasize to regional lymph nodes, peritoneum, ovaries, and lungs: Mammographically, isodense or hyperdense rounded or oval mass with circumscribed margins without architectural distortion and microcalcifications. On ultrasound, hypoechoic or mixed echogenic rounded or oval mass with posterior acoustic enhancement increased vascular flow and was frequently associated with axillary lymphadenopathy. Histopathology shows features of signet-ring cells with mitosis and nuclear atypia [Figure 8]. Primary breast SRCC shows positive MUC1, CK7, estrogen receptor, E-cadherin, GATA3, CK20, and negative CDX2.
Malignant phyllodes are rare fibroepithelial neoplasms of the breast, representing about 0.3-0.9% of all breast cancers. Clinically, it presents as a rapidly growing, painless, firm breast mass in women between 35 and 55. Axillary lymphadenopathy is unusual. On imaging, phyllodes tumors closely mimic fibroadenomas and may delay the diagnosis of malignancy. Mammographically, circumscribed, hyperdense mass with lucent halo, and may have associated microcalcifications. On ultrasonography, they are mixed echoic or hypoechoic, rounded mass with circumscribed or microlobulated margins, intralesional cysts, and clefts with posterior acoustic enhancement. On color doppler, mass frequently displays increased vascular flow [Figure 9]. Histologically, they demonstrate hypercellular stromal tissue and nuclear atypia with a high mitotic index. The treatment is surgical excision of the mass with margins exceeding 1 cm as the risk of recurrence is high.
Mesenchymal primary breast sarcomas are rare, accounting for less than 1% of all breast cancers, and liposarcoma accounts for 0.3% of breast sarcomas. Clinically, liposarcoma presents as a palpable breast mass which may closely mimic benign lesion on mammography as circumscribed, rounded or oval mass in the anterior third of breast. Calcifications may be present within the mass. Ultrasonographically, hyperechoic or mixed echogenic, oval, parallel mass with intralesional vascularity. On CT scan, isodense mass to muscle with hypodense fat density and variable enhancement after contrast enhancement [Figure 10]. On MRI, heterogeneous signal with high-intensity areas on T1 and T2WI and suppression of signal on fat saturation sequence and heterogeneous enhancement after contrast enhancement. Histology shows lobules of adipocytes with atypical stromal cells. Liposarcomas in the breast are usually well-differentiated/low-grade cancer and exhibit favorable outcomes compared to other sarcomas. The treatment is surgical excision.
Extraskeletal Ewing’s sarcoma (EES) is rare (reported as isolated case reports). It is a malignant soft tissue tumor occurring in adolescents and young adults between 10 and 30 years of age. Clinically, the patient presents with a rapidly progressing painless palpable breast lump with a high recurrence rate. Imaging modalities help in diagnosis, but the findings are non-specific. They are usually seen as a large circumscribed hyperdense mass without calcifications on mammography and on ultrasound, circumscribed homogeneous or heterogeneous hypoechoic mass with posterior acoustic enhancement. CT and MRI help identify the fat plane with the chest wall, usually preserved in ES arising from the breast [Figure 11]. Contrast-enhanced CT shows heterogeneous enhancement with non-enhancing hypodense areas of necrosis. PET/CT shows intense FDG activity in the enhancing regions. MRI shows low to isointense signal to muscle on T1-weighted images, hyperintense on T2-weighted images, and heterogeneous enhancement after gadolinium contrast administration. Histopathology shows malignant round cells, and immunohistochemistry confirms the diagnosis by demonstrating CD-99 membrane and FL1 nuclear positivity.
Medullary carcinoma of the breast is another rare invasive breast malignancy and accounts for less than 5% of all breast cancers. Compared to patients with infiltrating ductal carcinoma, medullary carcinoma patients tend to be relatively young and have a better prognosis with 10-year survival rates up to 84. Grossly, medullary carcinoma is usually a large distinct mass, firm in consistency with a circumscribed margin. The larger masses may have cystic change within. Medullary carcinoma can be mistaken clinically and radiologically for benign breast masses, e.g., fibroadenoma.
Medullary carcinoma is usually a non-calcified mass with indistinct or circumscribed margins on mammography and a circumscribed mass with an inhomogeneous hypoechoic echotexture on ultrasound examination [Figure 12]. On MRI, medullary carcinomas are usually oval or round-shaped masses with circumscribed margins and show rim enhancement of plateau or washout pattern on a kinetic curve with or without enhancing internal septations.
Breast malignancies with circumscribed margins and rounded or oval shapes are not always benign. Many unusual breast cancers can present with less aggressive features on imaging and mimic benign breast lesions such as fibroadenomas. Hence, it is essential to be aware of rare breast cancers' clinical and imaging features to avoid misdiagnosis or delayed diagnosis. All breast masses should be carefully assessed on imaging for other associated and subtle features such as mammogram calcifications, microlobulated margins and axillary lymphadenopathy on the US, intralesional vascular flow on color doppler, and lesion stiffness on elastography. Contrast-enhanced breast MRI may be added to characterize the functional as well as morphological aspects of the mass in more detail, which would be further helpful in the differentiation of benign and malignant breast masses. Core biopsy and immunohistochemical examinations are essential for diagnostic confirmation and therapeutic planning; hence, they should always be recommended in circumscribed breast masses with any degree of suspicion on imaging.
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