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Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings
Clinical Radiology xxx (xxxx) xxx
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Pictorial Review
Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings R. Pintican a, b, *, M. Duma a, c, A. Chiorean a, d, B. Fetica e, M. Badan e, V. Bura b, M. Szep d, D. Feier a, d, S. Dudea a, b a
Department of Radiology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania Radiology and Medical Imaging Department, University Hospital, Cluj-Napoca, Romania c Micromedica Clinic, Piatra Neamt, Romania d Medimages Breast Center, Cluj-Napoca, Romania e Pathology Department, University Hospital, Cluj-Napoca, Romania b
art icl e i nformat ion Article history: Received 27 September 2019 Accepted 31 December 2019
Mucinous and medullary breast cancers (BCs) have different histological substrates that manifest as different imaging features on mammography, ultrasound, and MRI. The aim of the present review is to demonstrate the differences between these two rare BC subtypes and to describe the microscopic features, review the imaging methods for detection of both cancer subtypes, illustrate the imaging findings and present useful pearls and pitfalls. Out of a total of 30 patients with mucinous BC and nine with medullary BC, we have selected typical and also unusual imaging features that best represent these cancers. The patients underwent a mammography and breast ultrasound followed by magnetic resonance imaging. We briefly exhibit histological characteristics for a better understanding of the imaging aspects. Ó 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Breast cancer (BC) represents the most common malignancy in women, accounting for 25% of all diagnosed malignancies.1 BC detection is related to mammographic screening.2 Occasionally, the diagnosis may be delayed on mammography, especially for malignant tumours that display pseudo-benign imaging features. Up to 20% of the circumscribed breast masses depicted on imaging are malignant tumours histologically.3 Among them are rare entities such as mucinous, medullary, and metaplastic cancers or the malignant phyllodes variant.3
Mucinous and medullary BCs are very rare subtypes, encountered in <5% of cases for mucinous and <1% for the medullary category.4 These tumours can occasionally be confused with one another or misdiagnosed due mostly to their pseudo-benign imaging appearances. This paper aims to present mucinous and medullary breast carcinoma, in antithesis, from histopathology to imaging aspects.
General overview Mucinous BC tends to occur more frequently in older women (>75 years), while the medullary type affects a
* Guarantor and correspondent: P. Roxana, University Hospital, Radiology and Medical Imaging Department, Cluj-Napoca, Romania.Tel.: +40729121122. E-mail address: [email protected] (R. Pintican). https://doi.org/10.1016/j.crad.2019.12.024 0009-9260/Ó 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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younger group (45e55 years), the latter with 10% of the cases diagnosed in women <35 years.5,6 On clinical examination, both cancer types may present as palpable breast lumps. Axillary metastases are rare in mucinous tumours (13%) and more common in medullary cancers (44%).6,7 Both BC subtypes have a good prognosis, with a 5-year overall survival that reaches 98.9% for mucinous and 89% for medullary tumours.8,9 Mixed mucinous carcinoma and its controversial classification and requires special attention. Although some authors have highlighted that mixed mucinous carcinoma is genomically distinct from invasive ductal carcinoma (IDC) and may be best classified as a variant of mucinous cancer, a poor outcome have been reported for this, which was similar to IDC.10,11
some institutions separate typical from atypical medullary carcinoma, there are no reported differences in prognosis or survival rates between the two medullary subtypes.14 At immunohistochemistry, the majority of mucinous tumours are molecularly classified as luminal A, being positive for oestrogen (ER, 94%), progesterone (PR, 82%) receptors and negative for HER-2/neu 15. Medullary cancers are defined by the negativity of all three markers in up to 92% of the cases, representing a triple-negative subset of BC.6
Imaging findings
BRCA1-positive patients are more likely to develop mucinous and medullary BC compared to the general population.5 BRCA1 mutation carriers have a significantly higher incidence of medullary BC, compared to non-carriers (13%, p<0.0001).12
The different histology of mucinous and medullary BCs translates into different imaging findings. Regarding the Breast Imaging-Reporting and Data System (BIRADS), the majority of pure mucinous tumours are categorised as follows: BIRADS 4C (43%) on mammography, BIRADS 4B (33,3%) or 4C (33,3%) on ultrasound, and BIRADS 5 (50%) on MRI.16 As for the medullary subtype, tumours are commonly classified as BIRADS 4 on mammography and ultrasound; to the authors’ knowledge, no studies have been published regarding the attributed BIRADS on MRI.17
Histology and immunohistochemistry
Mammography
Mucinous BC is defined by the presence of two major characteristics: (1) homogeneous groups of tumour cells and (2) excessive extracellular mucus lakes, occupying >90% of the tumour volume in the pure form (PMC) and <90% in the mixed form (MMC).13 Mixed mucinous carcinoma may be encountered together with other BC subtypes such as IDC or lobular cancer. Mucinous tumours are classified as type A (hypocellular, abundant mucin), type B (hypercellular or with neuroendocrine differentiation), or type AB (intermediate form). Medullary BC is defined by four main characteristics: (1) poorly differentiated cells, with (2) syncytial growth pattern, (3) lymphoplasmacytic reaction, and (4) a noninvasive microscopic circumscription13 (Fig 1). Tumours that do not fulfil all four criteria (previously named atypical medullary carcinoma) are, currently, contained within the term of “carcinoma with medullary features”.13 Although
Mass
Genetic characteristics
Pure mucinous and medullary BCs display similar mammographic findings; therefore, differentiation based only on mammography is not possible. The most frequently encountered mammographic feature in both BC subtypes is represented by solid mass (>92% for mucinous, 100% for medullary).18,19 The masses are frequently round or oval in shape, with circumscribed margins, resulting in a broad differential with benign lesions.3,15,18,19 In pure mucinous BC, a focal asymmetry of the breast tissue is encountered in up to 11% of the cases. In the medullary type, this finding is exceptionally rare.15,17
Margins Discordant data are reported regarding the margins of mucinous BC. Some authors describe circumscribed margins for all PMC and in a small proportion of MMC, while
Figure 1 Mucinous and medullary BC: histology. Haematoxylin and eosin stain displays the hypocellular type A (a) and hypercellular type B (b) pure mucinous type; medullary type (c) with a syncytial cells pattern, mitotic activity (circle) and surrounded by lymphocyte infiltrate (arrows). Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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others suggest that non-circumscribed margins (indistinct, microlobulate, or spiculate) represent dominant features in PMC (48%, 28%, and 42%).15,16,20 As a general tendency, indistinct and spiculate margins are considered suggestive of mixed mucinous cancers instead of the pure variant, although this finding does not reach statistical significance.16,20 Zhang et al. reported no differences between pure and mixed mucinous BCs in terms of tumour size, shape, margins, or accompanying microcalcifications.15 The conflicting literature data might be explained by dissimilar inclusion criteria and different histological distinction between pure and mixed counterparts, with various proportions of mucin attributed to the mixed subtype (<90%, 75e90%, 50e90%, <50%).15,16,20 Medullary tumours may also display non-circumscribed margins (obscured, microlobulate, indistinct, or spiculate) and sometimes a partial or complete lucent halo sign is observed17,19 (Fig 2).
Density Both BC subtypes frequently present as equal- or highdensity masses compared to the normal fibroglandular tissue.16,19 High variability is encountered in the mucinous type, where studies suggest that tumour density might be correlated with the amount of mucin16: a hypocellular tumour with abundant mucin appears more translucent compared to a more opaque hypercellular tumour with small amount of mucin (Fig 3). The high mucin content found in certain masses might explain why up to 20% of the mucinous tumours are occult on mammography.18,21
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carcinoma may be highlighted as a suspicious cluster of microcalcifications as the unique sign of malignancy.22 Microcalcifications are secondary to ductal carcinoma in situ but may also be identified inside acellular mucin (Fig 4)
Ultrasound Both BC subtypes may be easily misdiagnosed as benign lesions due to their ultrasound appearance.
Shape The shape of the tumour is often oval for mucinous (42% of the cases) and oval or round for medullary carcinoma, although both cancers may likewise present as irregular masses.16 When oval, both BC subtypes are usually oriented parallel to the skin’s surface (Fig 5).
Margins Both pure mucinous and medullary carcinoma usually display a circumscribed border. Both types of cancers may show non-circumscribed margins, either indistinct or microlobulate (50% of PMC, 33.3% of MMC and rarely for medullary cases; Fig 6).16,17,19,20
Echogenicity For the mucinous type, as the mammography density is influenced by the mucin quantity, so is the lesion echogenicity. A pure, hypocellular type A mass is as isoechoic with the subcutaneous fat while a more cellular type B mass tends to be slightly hypoechoic.20 The highly packed cellularity of the medullary type is responsible for the tumour’s intense hypoechoic appearance19 (Fig 7).
Microcalcifications Microcalcifications are not characteristic for mucinous or for medullary BC. Both types of cancer may rarely present with small, round, or amorphous calcifications, usually accompanied by a mass or focal asymmetry.15,19 The presence of microcalcifications suggests a mixed tumour instead of the pure mucinous BC (44% versus 33%).15 In cases of mixed mucinous tumour, which is extremely rare, the
Echo-structure The echo-structure is commonly reported as homogeneous for both BC subtypes.17,18,20 Heterogeneous lesions may be encountered in both pure mucinous and medullary BC.16,19 One third of the pure mucinous tumours may present as a complex mass with cystic and solid components18 (Figs 8e10).
Figure 2 Mammography appearances of mucinous and medullary BC. Craniocaudal (CC) views of (a) mucinous and (b) medullary cancers presented as circumscribed masses, without calcifications. CC views of (c) mucinous and (d) medullary tumours presented as non-circumscribed masses with partly obscured margins (arrowhead) respectively indistinct and slightly spiculate margins (arrow). Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 3 Mucinous tumours with different densities at mammography. Mediolateral oblique (MLO) views showing mucinous tumours (arrows): as a (a) high-density mass (hypercellular type B), (b) equal-density mass (hypocellular type A), (c) low-density mass (hypocellular type A) and (d,e) to the mammographic occult breast lesion (MLO and CC views of the same patient) but with (d) positive axillary lymphadenopathy (arrow). Also note the various margins: (a) circumscribed, (b) spiculate, (c) angular.
Figure 4 Rare findings in mucinous BC. (a) Mucinous tumour presented as a mass with microcalcifications. (b) Bifocal mucinous tumour seen as two distinctive circumscribed masses. (c) Patient with mammographic visible tumour and axillary lymphadenopathy.
In mixed mucinous tumour, the most frequently encountered aspect is represented by a hypoechoic lesion (50e100%), which is more heterogeneous when compared to the pure mucinous type, occasionally with cystic changes11,13,16 (Fig 11).
Calcifications The calcifications inside a mass, or associated features such as duct changes, skin changes, or oedema, are seldom reported for both BC subtypes.19
Vascularisation Posterior features Acoustic enhancement is usually seen in both BC subtypes, although for small lesions, no change in the distal echo amplitude might be observed.16,19,20 Compared to the mucinous type, the medullary tumour may occasionally exhibit shadowing.19 Additionally, a combined pattern of enhancement and attenuation is possible for large, heterogeneous lesions of both mucinous and medullary types.
The vascularisation using colour or power Doppler shows a distinctive flow signal for mucinous and medullary BC. Although the medullary tumour typically displays rim vessels, there are conflicting data about the vascularity of mucinous tumours. Some authors report mild and diffusely distributed vascularity, while others report up to 67% of the tumours with absent Doppler signal.16,18,19
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 5 Pseudobenign ultrasound appearance of mucinous and medullary tumours. (a) Mucinous BC presents as a circumscribed, lobulate, isoechoic mass, (b) hypovascular, and (c) mixed on elastography. Medullary tumour observed as an (d) intense hypoechoic lesion with microlobulate margins, (e) intense peripheral vascularity, and (f) mixed signal on elastography.
Figure 6 Non-circumscribed margins. Type A and type B mucinous BC presents as (a,d) hypoechoic masses with non-circumscribed margins, (b) mild and (e) moderate vascularisation and (c,f) hard on elastography. Medullary tumour shows a more hypoechoic mass with indistinct margins, acoustic enhancement and (g) marginal shadowing, (h) internal vascularity, and (i) soft elastography appearance. (j) Core needle biopsy was performed.
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 7 Different echogenicity. (a) Type A (arrows), (b) type B mucinous, and (c) medullary tumour, together with their corresponding histological images: (d) hypocellular mucinous, (e) hypercellular mucinous, (f) medullary type. Note how the echogenicity decreases with increasing tumour cellularity.
Figure 8 Heterogeneous mass appearance of mucinous cancer. Both patients have mucinous BCs. First, (a) a lobulate, hypoechoic, heterogeneous mass with predominantly solid components (yellow arrow), small cystic area (green arrow), and multiple hyperechoic foci (white arrow), confirmed as microcalcifications on mammography. (b) The mass has diffuse, central vascularisation and (c) is hard on elastography. Second, (d) heterogeneous mass with solid component (yellow arrow) cystic areas (green arrows), and (e) mild vascularisation. (f) This time, due to the predominance of cystic areas, the mass is soft on elastography. Also note the acoustic enhancement produced by the two masses.
Elastography Mucinous and medullary cancers may encompass a wide range of elastography scores, from soft to hard appearances, especially for medullary tumours (Figs 12 and 13). Elastography may also be useful in detecting a hardly visible
isoechoic lesion (Fig 14). To the authors’ knowledge, there are conflicting data about the shear-wave elastography (SWE) or acoustic radiation force impulse (ARFI) imaging in mucinous and medullary BCs, and further studies are required for a conclusion.23e27
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 9 Heterogeneous masses of mucinous and medullary BC. (a) Mucinous BC detected as a heterogeneous mass, with solid (yellow arrow) and cystic components (green arrow), mild vascularisation (b), and (c) mixed on elastography. (d) Medullary BC observed as a circumscribed, intense hypoechoic, heterogeneous mass with solid (yellow arrow) and cystic (green arrow) components. (e,f) The mass has predominantly peripheral vascularisation and is soft on elastography (g).
Figure 10 “Non-mass” US appearance of mucinous BC. (a,d) Two pure mucinous BCs presented as “non-mass” lesions, without identifiable margins, heterogeneous, with solid (white arrows) and cystic (green arrows) components. The areas were (b,e) vascularised, with (c) hard and (f) mixed elastography appearances.
Contrast-enhanced ultrasound (CEUS) The majority of mucinous BCs display a heterogeneous pattern on CEUS and, rarely, the absence of enhancement might be noted, while the majority of medullary BCs display a homogeneous enhancement pattern on CEUS.28,29 The molecular subtypes might be suggested by certain
ultrasound findings. The triple-negative medullary tumour may be suspected when a round, intensely hypoechoic mass with rim vascularity and soft appearance is encountered.30,31 The luminal A tumour is linked to hypoechoic masses with spiculate margins and echogenic halo, an appearance that is not representative for pure mucinous tumours.
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 11 Mixed mucinous types. Mixed mucinous BC, presented as hypoechoic masses with (a,d) spiculate margins, (b,e) vascularised and (c,f) hard on elastography. Note that both masses display a subtle hyperechoic rim on B mode.
Figure 12 Elastography appearance. (a,b) Two mucinous type lesions (arrows) that were soft and hard on elastography (Tsukuba score 1 and 5), respectively. (c,d) Two medullary type lesions (arrows) that were hard on elastography and mixed on elastography (Tsukuba score 4 and 3), respectively.
Magnetic resonance imaging Magnetic resonance imaging (MRI) is recommended to reveal tumour extension and to highlight multifocal or bilateral lesions. Mucinous and medullary BCs have the
same incidence of multicentricity, with more than one mass found in up to 10% of the cases.6,18 Up to 38% of the patients with mucinous tumour have multifocal/multicentric disease that is occult at mammography and ultrasound.21
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 13 BGR elastography. Blueegreenered (BGR) appearance may be rarely observed in both mucinous (a,b,c) and medullary (d,e,f) BC types.
Figure 14 Hardly visible lesions on B-mode. (a,b,c) Mucinous BC lesions that are barely visible on B mode, but are easily depicted using elastography (Tsukuba score 4). (d) A small medullary lesion better highlighted with elastography (Tsukuba score 4).
MRI depicts mass enhancement in the majority of cases (>84% for both mucinous and medullary BC), and rarely, a non-mass enhancement pattern (<17% for PMC and MMC).16
The MRI sequences that enable discrimination between mucinous and medullary BCs may be grouped into three main categories as follows: T2-weighted including fat
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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saturated imaging, apparent diffusion coefficient (ADC) on diffusion-weighted imaging (DWI), and contrast-enhanced sequences.
T2/T2-weighted fat-saturated imaging MRI is crucial for mucinous cancer diagnosis, by highlighting the presence of a very intense T2 signal lesion as a key finding (up to 83% of the cases).16,32 The T2 signal remains hyperintense on fat-saturated sequences and is explained by the large amount of water contained within mucin. Other breast lesion constituents may exhibit high T2 signal, such as adipose or sebaceous tissue, cystic or necrotic components, and haemorrhagic changes, some of them with a signal drop on fat-saturated sequences. In the mixed mucinous type, the non-mucinous part, if large enough, will present with a low T2 signal and will induce a more heterogeneous tumour appearance.32,33 Zhang et al. reported no statistical differences between pure and mixed mucinous BC, in terms of T2 signal intensity, internal mass enhancement, or kinetic curve, concluding that all mucinous tumours presents as homogeneous or heterogeneous T2 hyperintense masses.15 The medullary type behaves as a typical invasive BC and has low signal intensity on both T2 and T2 fat saturated, occasionally with a visible hypointense rim, corresponding to a fibrous capsular component. Rarely the medullary type may display a slightly hyperintense T2 fat-saturated signal due to
Figure 15 Mucinous versus medullary T2 appearance. (a) Mucinous tumour with hyperintense T2 and (b) T2 fat-saturated signal in contrast to (c) the hypointense T2 and (d) T2 TIRM (turbo inversion recovery magnitude) medullary tumour. Note the bright rim visible on TIRM sequences, suggestive of adjacent oedema.
oedematous stroma or haemorrhage, but the signal will not reach the hyperintensity of the mucinous type.34 (Fig 15).
DWI/ADC Due to the low cellularity and abundant mucin, mucinous cancers do not restrict diffusion and have low signal intensity on DWI, corresponding to high ADC values. Some authors report ADC values higher than those corresponding to benign breast tumours (ADC >1.8103 mm2/s for mucinous cancer versus ADC >1.3103mm2/s for benign lesions).32,33 This finding is justified histologically: even if mucinous cancer and fibroadenoma have similar cell numbers, the water molecules move more randomly in a mucin pool than in a fibroadenoma or benign phyllodes interstitium.35 Compared to pure mucinous tumours, mixed tumours have a lower ADC, depending on the nonmucinous proportion of the tumour (ADC ranged from 0.7e1.1103 mm2/s).15 Medullary BC frequently exhibits restricted diffusion with high DWI signal and low ADC values (mean ADC value 0.89103 mm2/s36; Fig 16).
Contrast-enhanced sequences Enhancement patterns. Pure mucinous and medullary BCs frequently demonstrate mass enhancement with a pattern that sometimes appears to act opposite. In pure mucinous tumours, the enhancement pattern during the early phase varies with cellularity (type A and type B) respectively with the distribution of non-mucinous components in mixed tumours. In pure type A mucinous tumours, the contrast agent takes longer to diffuse through the mucin. This explains the early mild rim enhancement observed in these tumours, while in the delayed phase, a diffuse, heterogeneous enhancement pattern is noticed.32,37 In pure mucinous type B tumours, a strong and heterogeneous early enhancement is highlighted, which persists in the delayed phase.37 Non-enhancing internal fibrous septa might be seen in large tumours, on both early and delayed phases. Rarely, a pure mucinous tumour may exhibit no enhancement during the early phase with mild heterogeneous enhancement during the delayed phase.37 Regarding the mixed mucinous tumour, strong heterogeneous enhancement is frequently seen during the early and delayed phases. Thereby, pure mucinous tumour type B and mixed mucinous tumour may exhibit similar findings on dynamic MRI images and may be difficult to distinguish one from another. In contrast to the pure hypocellular mucinous type, the highly packed cells of the medullary tumour are more prone to necrosis and cystic degeneration, changes that may appear as a heterogeneous early enhancement pattern. In the absence of these histological changes, the tumour displays homogeneous enhancement during the early phase. Apart from the early phase, all medullary tumours exhibit rim enhancement during the delayed phase, explained most likely by the peripheral lymphoplasmacytic reaction, inflammatory changes, or by the rim of the compressed connective tissue34,38 (Fig 17). Non-mass enhancement may
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 16 DWI/ADC in mucinous versus medullary type. Mucinous tumour displays a (a) hyperintense T2 and (b) T2 fat-saturated appearance, with (c) a bright signal on DWI (arrow) and (d) ADC map (ADC >1.3103 mm/s) is indicative of no restricted diffusion. Medullary tumour exhibits a (e) hypointense T2 and (f) T2 fat-saturated appearance, with a (g) bright signal on DWI and (h) low signal on the ADC map (ADC ¼ 0.46103 mm/s) indicative of restricted diffusion.
Figure 18 Non-mass enhancement in mucinous BC. (a) T2 image without any notable changes. (b) On the T1-weighted post-contrast subtraction image, non-mass enhancement with segmental and linear distribution is depicted in the right breast. Histology revealed mucinous BC.
be observed in mucinous cancer as opposed to the medullary type and has a heterogeneous regional pattern, which corresponds to the extensive intraductal component37 (Fig 18).
Contrast kinetics
Figure 17 Opposite enhancement patterns. (a) Mucinous type displaying rim enhancement on early phase imaging with (b) tendency to homogeneous enhancement on the delayed phase. (c) Medullary type showing (c) a heterogeneous enhancement on the early phase with (d) peripheral, rim enhancement on the delayed phase.
Pure and mixed mucinous BC may be differentiated using MRI contrast medium kinetics. There is a gradual and persistent type I curve and sometimes type II curve for the pure type (83%), and a wash-out type III curve for the mixed type (75%).15,16 On dynamic studies, all medullary tumours present a rapid initial rise on timeeintensity curve with either a plateau or a wash-out kinetics (type II or III curves).34,38 The gradual enhancement curve (type I) frequently found in the pure mucinous type, has not been described in medullary tumours34,38 (Figs 19 and 20; Table 1).
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 19 Kinetic curves (Kuhl) in mucinous versus medullary tumours. (a,d,c) Mucinous tumour displaying a progressive and persistent enhancement consistent with type I curve. (d,e,f) Medullary tumour showing rapid initial rise followed by a drop-off (washout) in delayed phase, consistent with type III curve.
Figure 20 Atypical kinetic curves in mucinous and medullary tumours. (a,b) Mucinous tumour with a type III kinetic curve: rapid initial rise with “wash out” on delayed phases. (c,d) Medullary tumour with a type II kinetic curve: rapid initial rise followed by a plateau (a,b). Histology confirmed the mucinous (1) and medullary (2) BC.
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
R. Pintican et al. / Clinical Radiology xxx (xxxx) xxx Table 1 Differential features of mucinous and medullary breast cancers. Feature
Mucinous
Medullary
Clinical Age (years) Palpation
>75 Soft mass Rare Good
45e55 Rapidly growing mass More frequent Good
þ Luminal A
þþ Triple negative
4c 4b 5
4 4 No Data
þ þ
þ -
þ þ þ/-
þ þ
-
-
Oval Circumscribed Isoechoic ¼ hypocellular Homogeneous/ heterogeneous/ complex
Oval/round Circumscribed Intense hypoechoic
þ Mild/diffuse/absent All scores Not enough data Heterogeneous
þ þ Rim All scores Not enough data Homogeneous
þ þ HyperLow DWI/high ADC Early mild rim, heterogeneous delayed ¼ type A
þ Hypo-/hyperHigh DWI/low ADC Early heterogeneous/ homogeneous, rim on delayed
Axillary lymph node Survival Genetics BRCA1 Immunohistochemistry ACR BIRADS Mammography Ultrasound MRI Mammography Mass Focal asymmetry Margins Circumscribed Non-circumscribed Density: equal or high Microcalcifications Ultrasound Shape Margins Echogenicity Echo-structure
Posterior features Enhancement Shadowing Calcifications Vascularisation Elastography ARFI/SWE CEUS MRI Mass e enhancement Non-mass enhancement T2/T2-weighted fat saturated
DWI/ADC
Contrast Pattern Kinetics
Homogeneous/ heterogeneous
Strong, heterogeneous early, persistent ¼ type B Type I curve
Type II/ III curves
ACR BIRADS, American College of Radiology Breast Imaging-Reporting and Data System; SWE/ARFI, shear-wave elastography/acoustic radiation force impulse imaging; CEUS, contrast-enhanced ultrasound; DWI, diffusionweighted imaging; ADC, apparent diffusion coefficient.
Conclusion Mucinous and medullary BCs have different histological characteristics that manifest as different imaging features on mammography, ultrasound, and MRI.
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Conflict of interest The authors declare no conflict of interest.
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22. PinaInsausti LJ, Soga Garcia E. Mucinous breast carcinoma showing as a cluster of suspicious microcalcifications on mammography. Eur Radiol 1998;8:1666e8. 23. Evans A, Sim YT, Thomson K. Shear wave elastography of breast cancer: sensitivity according to histological type in a large cohort. Breast 2016;26:115e8. https://doi.org/10.1016/j.breast.2016.01.009. 24. Li TT, Kang CS, Li HZ, et al. Value of shear wave elastrography image classification in the diagnosis of breast masses. Zhonghua Zhong Liu Za Zhi 2019;23(41):540e5. https://doi.org/10.3760/cma.j.issn.02533766.2019.07.011. 25. Kim SJ, Kyung HK, Hae K, et al. Shear wave elastography: is it a valuable additive method to conventional ultrasound for the diagnosis of small (2 cm) breast cancer? Medicine 2015;94:e1540, https://doi.org/ 10.1097/MD.0000000000001540. 26. Jin ZQ, Li XR, Zhou HL, et al. Acoustic radiation force impulse elastography of breast imaging reporting and data system category 4 breast lesions. Clin Breast Cancer 2012;12:420e7. https://doi.org/10.1016/ j.clbc.2012.07.007. 27. Li Dan-Dan, Guo Le-Hang, Xu Hui-Xiong, et al. Acoustic radiation force impulse elastography for differentiation of malignant and benign breast lesions: a meta-analysis. Int J Clin Exp Med 2015;8:4753e61. 28. Wang X, Xu P, Wang Y, et al. Contrast-enhanced ultrasonographic findings of different histopathologic types of breast cancer. Acta Radiol 2011;52:248e55. 29. Zhang Jian-xing, Cai Li-shan, Chen Ling. CEUS helps to rerate small breast tumors of BI-RADS Category 3 and Category 4. Biomed Res Int 2014:572532. https://doi.org/10.1155/2014/572532. 30. Zhang K, Li J, Shi Z, et al. Triple-negative invasive breast carcinoma: the association between the sonographic appearances with
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Pictorial Review
Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings R. Pintican a, b, *, M. Duma a, c, A. Chiorean a, d, B. Fetica e, M. Badan e, V. Bura b, M. Szep d, D. Feier a, d, S. Dudea a, b a
Department of Radiology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania Radiology and Medical Imaging Department, University Hospital, Cluj-Napoca, Romania c Micromedica Clinic, Piatra Neamt, Romania d Medimages Breast Center, Cluj-Napoca, Romania e Pathology Department, University Hospital, Cluj-Napoca, Romania b
art icl e i nformat ion Article history: Received 27 September 2019 Accepted 31 December 2019
Mucinous and medullary breast cancers (BCs) have different histological substrates that manifest as different imaging features on mammography, ultrasound, and MRI. The aim of the present review is to demonstrate the differences between these two rare BC subtypes and to describe the microscopic features, review the imaging methods for detection of both cancer subtypes, illustrate the imaging findings and present useful pearls and pitfalls. Out of a total of 30 patients with mucinous BC and nine with medullary BC, we have selected typical and also unusual imaging features that best represent these cancers. The patients underwent a mammography and breast ultrasound followed by magnetic resonance imaging. We briefly exhibit histological characteristics for a better understanding of the imaging aspects. Ó 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Breast cancer (BC) represents the most common malignancy in women, accounting for 25% of all diagnosed malignancies.1 BC detection is related to mammographic screening.2 Occasionally, the diagnosis may be delayed on mammography, especially for malignant tumours that display pseudo-benign imaging features. Up to 20% of the circumscribed breast masses depicted on imaging are malignant tumours histologically.3 Among them are rare entities such as mucinous, medullary, and metaplastic cancers or the malignant phyllodes variant.3
Mucinous and medullary BCs are very rare subtypes, encountered in <5% of cases for mucinous and <1% for the medullary category.4 These tumours can occasionally be confused with one another or misdiagnosed due mostly to their pseudo-benign imaging appearances. This paper aims to present mucinous and medullary breast carcinoma, in antithesis, from histopathology to imaging aspects.
General overview Mucinous BC tends to occur more frequently in older women (>75 years), while the medullary type affects a
* Guarantor and correspondent: P. Roxana, University Hospital, Radiology and Medical Imaging Department, Cluj-Napoca, Romania.Tel.: +40729121122. E-mail address: [email protected] (R. Pintican). https://doi.org/10.1016/j.crad.2019.12.024 0009-9260/Ó 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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younger group (45e55 years), the latter with 10% of the cases diagnosed in women <35 years.5,6 On clinical examination, both cancer types may present as palpable breast lumps. Axillary metastases are rare in mucinous tumours (13%) and more common in medullary cancers (44%).6,7 Both BC subtypes have a good prognosis, with a 5-year overall survival that reaches 98.9% for mucinous and 89% for medullary tumours.8,9 Mixed mucinous carcinoma and its controversial classification and requires special attention. Although some authors have highlighted that mixed mucinous carcinoma is genomically distinct from invasive ductal carcinoma (IDC) and may be best classified as a variant of mucinous cancer, a poor outcome have been reported for this, which was similar to IDC.10,11
some institutions separate typical from atypical medullary carcinoma, there are no reported differences in prognosis or survival rates between the two medullary subtypes.14 At immunohistochemistry, the majority of mucinous tumours are molecularly classified as luminal A, being positive for oestrogen (ER, 94%), progesterone (PR, 82%) receptors and negative for HER-2/neu 15. Medullary cancers are defined by the negativity of all three markers in up to 92% of the cases, representing a triple-negative subset of BC.6
Imaging findings
BRCA1-positive patients are more likely to develop mucinous and medullary BC compared to the general population.5 BRCA1 mutation carriers have a significantly higher incidence of medullary BC, compared to non-carriers (13%, p<0.0001).12
The different histology of mucinous and medullary BCs translates into different imaging findings. Regarding the Breast Imaging-Reporting and Data System (BIRADS), the majority of pure mucinous tumours are categorised as follows: BIRADS 4C (43%) on mammography, BIRADS 4B (33,3%) or 4C (33,3%) on ultrasound, and BIRADS 5 (50%) on MRI.16 As for the medullary subtype, tumours are commonly classified as BIRADS 4 on mammography and ultrasound; to the authors’ knowledge, no studies have been published regarding the attributed BIRADS on MRI.17
Histology and immunohistochemistry
Mammography
Mucinous BC is defined by the presence of two major characteristics: (1) homogeneous groups of tumour cells and (2) excessive extracellular mucus lakes, occupying >90% of the tumour volume in the pure form (PMC) and <90% in the mixed form (MMC).13 Mixed mucinous carcinoma may be encountered together with other BC subtypes such as IDC or lobular cancer. Mucinous tumours are classified as type A (hypocellular, abundant mucin), type B (hypercellular or with neuroendocrine differentiation), or type AB (intermediate form). Medullary BC is defined by four main characteristics: (1) poorly differentiated cells, with (2) syncytial growth pattern, (3) lymphoplasmacytic reaction, and (4) a noninvasive microscopic circumscription13 (Fig 1). Tumours that do not fulfil all four criteria (previously named atypical medullary carcinoma) are, currently, contained within the term of “carcinoma with medullary features”.13 Although
Mass
Genetic characteristics
Pure mucinous and medullary BCs display similar mammographic findings; therefore, differentiation based only on mammography is not possible. The most frequently encountered mammographic feature in both BC subtypes is represented by solid mass (>92% for mucinous, 100% for medullary).18,19 The masses are frequently round or oval in shape, with circumscribed margins, resulting in a broad differential with benign lesions.3,15,18,19 In pure mucinous BC, a focal asymmetry of the breast tissue is encountered in up to 11% of the cases. In the medullary type, this finding is exceptionally rare.15,17
Margins Discordant data are reported regarding the margins of mucinous BC. Some authors describe circumscribed margins for all PMC and in a small proportion of MMC, while
Figure 1 Mucinous and medullary BC: histology. Haematoxylin and eosin stain displays the hypocellular type A (a) and hypercellular type B (b) pure mucinous type; medullary type (c) with a syncytial cells pattern, mitotic activity (circle) and surrounded by lymphocyte infiltrate (arrows). Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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others suggest that non-circumscribed margins (indistinct, microlobulate, or spiculate) represent dominant features in PMC (48%, 28%, and 42%).15,16,20 As a general tendency, indistinct and spiculate margins are considered suggestive of mixed mucinous cancers instead of the pure variant, although this finding does not reach statistical significance.16,20 Zhang et al. reported no differences between pure and mixed mucinous BCs in terms of tumour size, shape, margins, or accompanying microcalcifications.15 The conflicting literature data might be explained by dissimilar inclusion criteria and different histological distinction between pure and mixed counterparts, with various proportions of mucin attributed to the mixed subtype (<90%, 75e90%, 50e90%, <50%).15,16,20 Medullary tumours may also display non-circumscribed margins (obscured, microlobulate, indistinct, or spiculate) and sometimes a partial or complete lucent halo sign is observed17,19 (Fig 2).
Density Both BC subtypes frequently present as equal- or highdensity masses compared to the normal fibroglandular tissue.16,19 High variability is encountered in the mucinous type, where studies suggest that tumour density might be correlated with the amount of mucin16: a hypocellular tumour with abundant mucin appears more translucent compared to a more opaque hypercellular tumour with small amount of mucin (Fig 3). The high mucin content found in certain masses might explain why up to 20% of the mucinous tumours are occult on mammography.18,21
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carcinoma may be highlighted as a suspicious cluster of microcalcifications as the unique sign of malignancy.22 Microcalcifications are secondary to ductal carcinoma in situ but may also be identified inside acellular mucin (Fig 4)
Ultrasound Both BC subtypes may be easily misdiagnosed as benign lesions due to their ultrasound appearance.
Shape The shape of the tumour is often oval for mucinous (42% of the cases) and oval or round for medullary carcinoma, although both cancers may likewise present as irregular masses.16 When oval, both BC subtypes are usually oriented parallel to the skin’s surface (Fig 5).
Margins Both pure mucinous and medullary carcinoma usually display a circumscribed border. Both types of cancers may show non-circumscribed margins, either indistinct or microlobulate (50% of PMC, 33.3% of MMC and rarely for medullary cases; Fig 6).16,17,19,20
Echogenicity For the mucinous type, as the mammography density is influenced by the mucin quantity, so is the lesion echogenicity. A pure, hypocellular type A mass is as isoechoic with the subcutaneous fat while a more cellular type B mass tends to be slightly hypoechoic.20 The highly packed cellularity of the medullary type is responsible for the tumour’s intense hypoechoic appearance19 (Fig 7).
Microcalcifications Microcalcifications are not characteristic for mucinous or for medullary BC. Both types of cancer may rarely present with small, round, or amorphous calcifications, usually accompanied by a mass or focal asymmetry.15,19 The presence of microcalcifications suggests a mixed tumour instead of the pure mucinous BC (44% versus 33%).15 In cases of mixed mucinous tumour, which is extremely rare, the
Echo-structure The echo-structure is commonly reported as homogeneous for both BC subtypes.17,18,20 Heterogeneous lesions may be encountered in both pure mucinous and medullary BC.16,19 One third of the pure mucinous tumours may present as a complex mass with cystic and solid components18 (Figs 8e10).
Figure 2 Mammography appearances of mucinous and medullary BC. Craniocaudal (CC) views of (a) mucinous and (b) medullary cancers presented as circumscribed masses, without calcifications. CC views of (c) mucinous and (d) medullary tumours presented as non-circumscribed masses with partly obscured margins (arrowhead) respectively indistinct and slightly spiculate margins (arrow). Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 3 Mucinous tumours with different densities at mammography. Mediolateral oblique (MLO) views showing mucinous tumours (arrows): as a (a) high-density mass (hypercellular type B), (b) equal-density mass (hypocellular type A), (c) low-density mass (hypocellular type A) and (d,e) to the mammographic occult breast lesion (MLO and CC views of the same patient) but with (d) positive axillary lymphadenopathy (arrow). Also note the various margins: (a) circumscribed, (b) spiculate, (c) angular.
Figure 4 Rare findings in mucinous BC. (a) Mucinous tumour presented as a mass with microcalcifications. (b) Bifocal mucinous tumour seen as two distinctive circumscribed masses. (c) Patient with mammographic visible tumour and axillary lymphadenopathy.
In mixed mucinous tumour, the most frequently encountered aspect is represented by a hypoechoic lesion (50e100%), which is more heterogeneous when compared to the pure mucinous type, occasionally with cystic changes11,13,16 (Fig 11).
Calcifications The calcifications inside a mass, or associated features such as duct changes, skin changes, or oedema, are seldom reported for both BC subtypes.19
Vascularisation Posterior features Acoustic enhancement is usually seen in both BC subtypes, although for small lesions, no change in the distal echo amplitude might be observed.16,19,20 Compared to the mucinous type, the medullary tumour may occasionally exhibit shadowing.19 Additionally, a combined pattern of enhancement and attenuation is possible for large, heterogeneous lesions of both mucinous and medullary types.
The vascularisation using colour or power Doppler shows a distinctive flow signal for mucinous and medullary BC. Although the medullary tumour typically displays rim vessels, there are conflicting data about the vascularity of mucinous tumours. Some authors report mild and diffusely distributed vascularity, while others report up to 67% of the tumours with absent Doppler signal.16,18,19
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 5 Pseudobenign ultrasound appearance of mucinous and medullary tumours. (a) Mucinous BC presents as a circumscribed, lobulate, isoechoic mass, (b) hypovascular, and (c) mixed on elastography. Medullary tumour observed as an (d) intense hypoechoic lesion with microlobulate margins, (e) intense peripheral vascularity, and (f) mixed signal on elastography.
Figure 6 Non-circumscribed margins. Type A and type B mucinous BC presents as (a,d) hypoechoic masses with non-circumscribed margins, (b) mild and (e) moderate vascularisation and (c,f) hard on elastography. Medullary tumour shows a more hypoechoic mass with indistinct margins, acoustic enhancement and (g) marginal shadowing, (h) internal vascularity, and (i) soft elastography appearance. (j) Core needle biopsy was performed.
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 7 Different echogenicity. (a) Type A (arrows), (b) type B mucinous, and (c) medullary tumour, together with their corresponding histological images: (d) hypocellular mucinous, (e) hypercellular mucinous, (f) medullary type. Note how the echogenicity decreases with increasing tumour cellularity.
Figure 8 Heterogeneous mass appearance of mucinous cancer. Both patients have mucinous BCs. First, (a) a lobulate, hypoechoic, heterogeneous mass with predominantly solid components (yellow arrow), small cystic area (green arrow), and multiple hyperechoic foci (white arrow), confirmed as microcalcifications on mammography. (b) The mass has diffuse, central vascularisation and (c) is hard on elastography. Second, (d) heterogeneous mass with solid component (yellow arrow) cystic areas (green arrows), and (e) mild vascularisation. (f) This time, due to the predominance of cystic areas, the mass is soft on elastography. Also note the acoustic enhancement produced by the two masses.
Elastography Mucinous and medullary cancers may encompass a wide range of elastography scores, from soft to hard appearances, especially for medullary tumours (Figs 12 and 13). Elastography may also be useful in detecting a hardly visible
isoechoic lesion (Fig 14). To the authors’ knowledge, there are conflicting data about the shear-wave elastography (SWE) or acoustic radiation force impulse (ARFI) imaging in mucinous and medullary BCs, and further studies are required for a conclusion.23e27
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 9 Heterogeneous masses of mucinous and medullary BC. (a) Mucinous BC detected as a heterogeneous mass, with solid (yellow arrow) and cystic components (green arrow), mild vascularisation (b), and (c) mixed on elastography. (d) Medullary BC observed as a circumscribed, intense hypoechoic, heterogeneous mass with solid (yellow arrow) and cystic (green arrow) components. (e,f) The mass has predominantly peripheral vascularisation and is soft on elastography (g).
Figure 10 “Non-mass” US appearance of mucinous BC. (a,d) Two pure mucinous BCs presented as “non-mass” lesions, without identifiable margins, heterogeneous, with solid (white arrows) and cystic (green arrows) components. The areas were (b,e) vascularised, with (c) hard and (f) mixed elastography appearances.
Contrast-enhanced ultrasound (CEUS) The majority of mucinous BCs display a heterogeneous pattern on CEUS and, rarely, the absence of enhancement might be noted, while the majority of medullary BCs display a homogeneous enhancement pattern on CEUS.28,29 The molecular subtypes might be suggested by certain
ultrasound findings. The triple-negative medullary tumour may be suspected when a round, intensely hypoechoic mass with rim vascularity and soft appearance is encountered.30,31 The luminal A tumour is linked to hypoechoic masses with spiculate margins and echogenic halo, an appearance that is not representative for pure mucinous tumours.
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 11 Mixed mucinous types. Mixed mucinous BC, presented as hypoechoic masses with (a,d) spiculate margins, (b,e) vascularised and (c,f) hard on elastography. Note that both masses display a subtle hyperechoic rim on B mode.
Figure 12 Elastography appearance. (a,b) Two mucinous type lesions (arrows) that were soft and hard on elastography (Tsukuba score 1 and 5), respectively. (c,d) Two medullary type lesions (arrows) that were hard on elastography and mixed on elastography (Tsukuba score 4 and 3), respectively.
Magnetic resonance imaging Magnetic resonance imaging (MRI) is recommended to reveal tumour extension and to highlight multifocal or bilateral lesions. Mucinous and medullary BCs have the
same incidence of multicentricity, with more than one mass found in up to 10% of the cases.6,18 Up to 38% of the patients with mucinous tumour have multifocal/multicentric disease that is occult at mammography and ultrasound.21
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 13 BGR elastography. Blueegreenered (BGR) appearance may be rarely observed in both mucinous (a,b,c) and medullary (d,e,f) BC types.
Figure 14 Hardly visible lesions on B-mode. (a,b,c) Mucinous BC lesions that are barely visible on B mode, but are easily depicted using elastography (Tsukuba score 4). (d) A small medullary lesion better highlighted with elastography (Tsukuba score 4).
MRI depicts mass enhancement in the majority of cases (>84% for both mucinous and medullary BC), and rarely, a non-mass enhancement pattern (<17% for PMC and MMC).16
The MRI sequences that enable discrimination between mucinous and medullary BCs may be grouped into three main categories as follows: T2-weighted including fat
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saturated imaging, apparent diffusion coefficient (ADC) on diffusion-weighted imaging (DWI), and contrast-enhanced sequences.
T2/T2-weighted fat-saturated imaging MRI is crucial for mucinous cancer diagnosis, by highlighting the presence of a very intense T2 signal lesion as a key finding (up to 83% of the cases).16,32 The T2 signal remains hyperintense on fat-saturated sequences and is explained by the large amount of water contained within mucin. Other breast lesion constituents may exhibit high T2 signal, such as adipose or sebaceous tissue, cystic or necrotic components, and haemorrhagic changes, some of them with a signal drop on fat-saturated sequences. In the mixed mucinous type, the non-mucinous part, if large enough, will present with a low T2 signal and will induce a more heterogeneous tumour appearance.32,33 Zhang et al. reported no statistical differences between pure and mixed mucinous BC, in terms of T2 signal intensity, internal mass enhancement, or kinetic curve, concluding that all mucinous tumours presents as homogeneous or heterogeneous T2 hyperintense masses.15 The medullary type behaves as a typical invasive BC and has low signal intensity on both T2 and T2 fat saturated, occasionally with a visible hypointense rim, corresponding to a fibrous capsular component. Rarely the medullary type may display a slightly hyperintense T2 fat-saturated signal due to
Figure 15 Mucinous versus medullary T2 appearance. (a) Mucinous tumour with hyperintense T2 and (b) T2 fat-saturated signal in contrast to (c) the hypointense T2 and (d) T2 TIRM (turbo inversion recovery magnitude) medullary tumour. Note the bright rim visible on TIRM sequences, suggestive of adjacent oedema.
oedematous stroma or haemorrhage, but the signal will not reach the hyperintensity of the mucinous type.34 (Fig 15).
DWI/ADC Due to the low cellularity and abundant mucin, mucinous cancers do not restrict diffusion and have low signal intensity on DWI, corresponding to high ADC values. Some authors report ADC values higher than those corresponding to benign breast tumours (ADC >1.8103 mm2/s for mucinous cancer versus ADC >1.3103mm2/s for benign lesions).32,33 This finding is justified histologically: even if mucinous cancer and fibroadenoma have similar cell numbers, the water molecules move more randomly in a mucin pool than in a fibroadenoma or benign phyllodes interstitium.35 Compared to pure mucinous tumours, mixed tumours have a lower ADC, depending on the nonmucinous proportion of the tumour (ADC ranged from 0.7e1.1103 mm2/s).15 Medullary BC frequently exhibits restricted diffusion with high DWI signal and low ADC values (mean ADC value 0.89103 mm2/s36; Fig 16).
Contrast-enhanced sequences Enhancement patterns. Pure mucinous and medullary BCs frequently demonstrate mass enhancement with a pattern that sometimes appears to act opposite. In pure mucinous tumours, the enhancement pattern during the early phase varies with cellularity (type A and type B) respectively with the distribution of non-mucinous components in mixed tumours. In pure type A mucinous tumours, the contrast agent takes longer to diffuse through the mucin. This explains the early mild rim enhancement observed in these tumours, while in the delayed phase, a diffuse, heterogeneous enhancement pattern is noticed.32,37 In pure mucinous type B tumours, a strong and heterogeneous early enhancement is highlighted, which persists in the delayed phase.37 Non-enhancing internal fibrous septa might be seen in large tumours, on both early and delayed phases. Rarely, a pure mucinous tumour may exhibit no enhancement during the early phase with mild heterogeneous enhancement during the delayed phase.37 Regarding the mixed mucinous tumour, strong heterogeneous enhancement is frequently seen during the early and delayed phases. Thereby, pure mucinous tumour type B and mixed mucinous tumour may exhibit similar findings on dynamic MRI images and may be difficult to distinguish one from another. In contrast to the pure hypocellular mucinous type, the highly packed cells of the medullary tumour are more prone to necrosis and cystic degeneration, changes that may appear as a heterogeneous early enhancement pattern. In the absence of these histological changes, the tumour displays homogeneous enhancement during the early phase. Apart from the early phase, all medullary tumours exhibit rim enhancement during the delayed phase, explained most likely by the peripheral lymphoplasmacytic reaction, inflammatory changes, or by the rim of the compressed connective tissue34,38 (Fig 17). Non-mass enhancement may
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 16 DWI/ADC in mucinous versus medullary type. Mucinous tumour displays a (a) hyperintense T2 and (b) T2 fat-saturated appearance, with (c) a bright signal on DWI (arrow) and (d) ADC map (ADC >1.3103 mm/s) is indicative of no restricted diffusion. Medullary tumour exhibits a (e) hypointense T2 and (f) T2 fat-saturated appearance, with a (g) bright signal on DWI and (h) low signal on the ADC map (ADC ¼ 0.46103 mm/s) indicative of restricted diffusion.
Figure 18 Non-mass enhancement in mucinous BC. (a) T2 image without any notable changes. (b) On the T1-weighted post-contrast subtraction image, non-mass enhancement with segmental and linear distribution is depicted in the right breast. Histology revealed mucinous BC.
be observed in mucinous cancer as opposed to the medullary type and has a heterogeneous regional pattern, which corresponds to the extensive intraductal component37 (Fig 18).
Contrast kinetics
Figure 17 Opposite enhancement patterns. (a) Mucinous type displaying rim enhancement on early phase imaging with (b) tendency to homogeneous enhancement on the delayed phase. (c) Medullary type showing (c) a heterogeneous enhancement on the early phase with (d) peripheral, rim enhancement on the delayed phase.
Pure and mixed mucinous BC may be differentiated using MRI contrast medium kinetics. There is a gradual and persistent type I curve and sometimes type II curve for the pure type (83%), and a wash-out type III curve for the mixed type (75%).15,16 On dynamic studies, all medullary tumours present a rapid initial rise on timeeintensity curve with either a plateau or a wash-out kinetics (type II or III curves).34,38 The gradual enhancement curve (type I) frequently found in the pure mucinous type, has not been described in medullary tumours34,38 (Figs 19 and 20; Table 1).
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
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Figure 19 Kinetic curves (Kuhl) in mucinous versus medullary tumours. (a,d,c) Mucinous tumour displaying a progressive and persistent enhancement consistent with type I curve. (d,e,f) Medullary tumour showing rapid initial rise followed by a drop-off (washout) in delayed phase, consistent with type III curve.
Figure 20 Atypical kinetic curves in mucinous and medullary tumours. (a,b) Mucinous tumour with a type III kinetic curve: rapid initial rise with “wash out” on delayed phases. (c,d) Medullary tumour with a type II kinetic curve: rapid initial rise followed by a plateau (a,b). Histology confirmed the mucinous (1) and medullary (2) BC.
Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024
R. Pintican et al. / Clinical Radiology xxx (xxxx) xxx Table 1 Differential features of mucinous and medullary breast cancers. Feature
Mucinous
Medullary
Clinical Age (years) Palpation
>75 Soft mass Rare Good
45e55 Rapidly growing mass More frequent Good
þ Luminal A
þþ Triple negative
4c 4b 5
4 4 No Data
þ þ
þ -
þ þ þ/-
þ þ
-
-
Oval Circumscribed Isoechoic ¼ hypocellular Homogeneous/ heterogeneous/ complex
Oval/round Circumscribed Intense hypoechoic
þ Mild/diffuse/absent All scores Not enough data Heterogeneous
þ þ Rim All scores Not enough data Homogeneous
þ þ HyperLow DWI/high ADC Early mild rim, heterogeneous delayed ¼ type A
þ Hypo-/hyperHigh DWI/low ADC Early heterogeneous/ homogeneous, rim on delayed
Axillary lymph node Survival Genetics BRCA1 Immunohistochemistry ACR BIRADS Mammography Ultrasound MRI Mammography Mass Focal asymmetry Margins Circumscribed Non-circumscribed Density: equal or high Microcalcifications Ultrasound Shape Margins Echogenicity Echo-structure
Posterior features Enhancement Shadowing Calcifications Vascularisation Elastography ARFI/SWE CEUS MRI Mass e enhancement Non-mass enhancement T2/T2-weighted fat saturated
DWI/ADC
Contrast Pattern Kinetics
Homogeneous/ heterogeneous
Strong, heterogeneous early, persistent ¼ type B Type I curve
Type II/ III curves
ACR BIRADS, American College of Radiology Breast Imaging-Reporting and Data System; SWE/ARFI, shear-wave elastography/acoustic radiation force impulse imaging; CEUS, contrast-enhanced ultrasound; DWI, diffusionweighted imaging; ADC, apparent diffusion coefficient.
Conclusion Mucinous and medullary BCs have different histological characteristics that manifest as different imaging features on mammography, ultrasound, and MRI.
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Conflict of interest The authors declare no conflict of interest.
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Please cite this article as: Pintican R et al., Mucinous versus medullary breast carcinoma: mammography, ultrasound, and MRI findings, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.12.024