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Axillary Nodal Metastases in Invasive Lobular Carcinoma Versus Invasive Ductal Carcinoma: Comparison of Node Detection and Morphology by UltrasoundHannah L. Chung, MD, Hilda H. Tso, DO, Lavinia P. Middleton, MD, Jia Sun, PhD, Jessica W. T. Leung, MD

https://doi.org/10.2214/AJR.21.26135 Accepted: July 21, 2021 Article Type: Original Research

The complete title page, as provided by the authors, is available at the end of this article.

AbstractBackground: Invasive lobular carcinoma is more subtle on imaging compared with invasive ductal carcinoma; nodal metastases may also differ on imaging between these.

Objective: To determine whether invasive lobular carcinoma and invasive ductal carcinoma differ in the detection rate by ultrasound (US) of metastatic axillary nodes and in metastatic nodes’ US characteristics.

Methods: This retrospective study included 695 women (median age 53 years) with breast cancer in a total of 723 breasts (76 lobular, 586 ductal, 61 mixed), with biopsy-proven axillary nodal metastases and who underwent pretreatment US. A single breast radiologist reviewed US images in patients with suspicious nodes on US and classified node number, size, and morphology. Morphologic assess-ment used a previously described classification based on the relationship between node cortex and hilum. Nodal findings were com-pared between lobular and ductal carcinoma. A second radiologist independently classified node morphology in 241 cancers to assess interreader agreement.

Results: A total of 99 metastatic axillary nodes (15 lobular, 66 ductal, 18 mixed) were not visualized on US and were diagnosed by sur-gical biopsy. The remaining 624 metastatic nodes (61 lobular, 520 ductal, 43 mixed) were visualized on US and diagnosed by US-guided FNA. Thus, US detected the metastatic nodes in 80.3% for lobular carcinoma versus 88.7% for ductal carcinoma (p=.04). Among meta-static nodes detected by US, retrospective review identified ≥3 abnormal nodes in 50.8% of lobular carcinoma versus 69.2% of ductal carcinoma (p=.003); node size was ≤2.0 cm in 65.6% for lobular carcinoma versus 47.3% for ductal carcinoma (p=.03); morphology was type III/IV (diffuse cortical thickening without hilar mass effect) rather than type V/VI (marked cortical thickening with hilar mass effect) in 68.9% for lobular carcinoma versus 28.8% for ductal carcinoma (p<.001). Interreader agreement assessment for morphology exhibited kappa coefficient of 0.63 (95% CI, 0.54-0.73).

Conclusion: US detects a lower percentage of nodal metastases in lobular than ductal carcinoma. Nodal metastases in lobular carcino-ma more commonly show diffuse cortical thickening and with less hilar mass effect.

Clinical Impact: A lower threshold may be warranted to recommend biopsy of suspicious axillary nodes detected on US in patients with lobular carcinoma.

Recommended citation:Chung HL, Tso HH, Middleton LP, Sun J, Leung JWT. Axillary Nodal Metastases in Invasive Lobular Carcinoma Versus Invasive Ductal Carcinoma: Comparison of Node Detection and Morphology by Ultrasound. AJR 2021 Jul 28 [published online]. Accepted manuscript. doi:10.2214/AJR.21.26135D

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Highlights

Key Finding: • US has a lower detection rate (p=.04) for axillary nodal metastases in lobular carcinoma [80.3%

(61/76)] than in ductal carcinoma [88.7% (520/586)]. Metastatic nodes detected on US exhibited diffuse cortical thickening without hilar mass effect in 68.9% (42/61) for lobular carcinoma versus 28.8% (150/520) for ductal carcinoma (p<.001).

Importance: • A lower threshold may be warranted to recommend biopsy of suspicious axillary nodes detected

on US in patients with lobular than ductal carcinoma.

Introduction

Invasive lobular carcinoma, originating in the breast lobules rather than in the duct, is the

second most common form of epithelial breast cancer after invasive ductal carcinoma, accounting for

10-15% of all invasive breast cancer diagnoses [1]. Its incidence has increased in parallel with increasing

use in the United States of hormone replacement therapy [2]. Compared with ductal carcinoma, lobular

carcinoma is more often occult on imaging, attributed to the loss of E-cadherin, an epithelial cell-to-cell

adhesion molecule that allows tumor cells to coalesce [3]. Without E-cadherin expression, tumor cells

disperse into the surrounding stroma, with a propensity to infiltrate along pre-existing bands of fibrosis.

Lobular carcinoma is thus less likely to form discrete masses, elicit desmoplasia, or calcify [4]. Diagnosing

lobular carcinoma may be challenging as the physical examination, imaging findings, and pathologic

findings can be subtle and less specific compared with in ductal carcinoma.

Axillary ultrasound (US) with nodal biopsy is used to assess for the presence of nodal metastases

and to determine the extent of nodal involvement. As invasive lobular carcinoma and invasive ductal

carcinoma have different imaging appearances, it is plausible that nodal metastases from these two

epithelial carcinomas of the breast differ as well in their appearance on US. Indeed, a more subtle US

appearance for nodal metastases from invasive lobular carcinoma than for nodal metastases from

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invasive ductal carcinoma would be consistent with the difference in imaging appearance for the

primary cancers. Cortical morphology is a key US finding associated with a lymph node’s metastatic risk

and detection on US and potentially could be different between the two histologic types of breast

cancer [5]. The purpose of this study was to determine whether invasive lobular carcinoma and invasive

ductal carcinoma of the breast differ in terms of the detection rate by US of metastatic axillary lymph

nodes as well as in the US characteristics of metastatic axillary lymph nodes.

Methods

Patient Sample

This was a single-institution, HIPAA-compliant, institutional review board–approved,

retrospective study. The requirement for written informed consent was waived. We searched an

institutional database for patients diagnosed with invasive breast cancer and who had undergone a

breast US examination at our institution from January 2016 through January 2019, identifying a total of

1400 patients with 1432 invasive breast cancers (152 lobular, 1174 ductal, 106 mixed lobular and

ductal); 32 patients had bilateral breast cancer. A total of 709 cancers without biopsy-proven metastatic

axillary lymph nodes were excluded, leaving a final study sample of 723 cancers (76 lobular, 586 ductal,

61 mixed histology) with biopsy-proven nodal metastases in 695 patients (median age 53 years; range,

22-93 years). A total of 28 patients in this sample had bilateral nodal-metastatic breast cancers (7 with

bilateral invasive lobular, 13 with bilateral invasive ductal, 1 with bilateral mixed, and 7 with discordant

histology between the breasts). No patient received treatment before the US or biopsy.

For included patients, the electronic medical record (EMR) was reviewed to record tumor

characteristics. These included: grade, estrogen receptor (ER) status, human epidermal growth factor

(HER2) receptor status, and Ki67 proliferation index [categorized as low (≤14%), medium (15-34%) or

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high (≥35%)], T category (based on the primary tumor’s single longest dimension on the US examination)

and stage. The tumor grade, ER status, HER2 receptor status, and Ki67 proliferation index were used to

further stratify the cancers into four different molecular subtypes: luminal A, luminal B, HER2 enriched,

or triple-negative breast cancer [6]. Cancers were also classified based on imaging reports as unifocal

versus involving multiple sites within the breast (e.g., multifocal or multicentric). In cases of multifocal or

multicentric breast cancer, the size of the largest (i.e., index) carcinoma was used for recording tumor

size.

Reference Standard

At our institution, all women with newly diagnosed breast cancer undergo US evaluation to

assess for metastatic axillary lymph nodes. Nodes with a cortex measuring at least 3 mm are considered

indeterminate or suspicious [7]. Percutaneous US-guided fine needle aspiration (FNA) with cytologic

assessment is performed of all indeterminate or suspicious axillary nodes on US. The FNA procedures

are performed by one of approximately 37 faculty radiologists with fellowship training in breast imaging.

While the available equipment at our institution changed during the multiyear study period, most US

examinations were performed using a Philips EPIQ 5G ultrasound unit. The FNA procedure is performed

using a 21 gauge needle and one or two passes, with real-time cytologic assessment to ensure adequacy

of sampling, as indicated by the presence of lymphocytes. The procedure is planned based on nodal

assessment using static images in longitudinal and transverse planes, without consideration of Doppler

characteristics. Areas of focal nodal cortical thickening are targeted for FNA sampling; for nodes with

diffuse cortical thickening without focal lobulation, the cortex is randomly sampled. Surgical sentinel

lymph node biopsy is performed in patients without indeterminate or suspicious nodes on initial staging

US and in patients with a benign FNA result.

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Image Analysis

A single breast imaging radiologist with 12 years of post-fellowship experience (HT) reviewed

the US images in all patients with indeterminate or suspicious nodes. This reader was aware that

patients had breast cancer with nodal metastases, but was blinded to whether the patient had invasive

lobular or ductal carcinoma. The US images were reviewed for the number (classified as 1 or 2 versus

≥3), size (longest single dimension, classified as ≤2.0 cm, 2.1-4.0 cm, or ≥4.0 cm), and morphology of the

indeterminate or suspicious node. In patients with multiple indeterminate or suspicious nodes, the size

and morphology of the most suspicious-appearing node was recorded. Nodal morphology was classified

as one of type III through type VI (Figure 1), using the system proposed by Bedi et al [5]. Type III and IV

nodes exhibit hypoechoic cortical thickening measuring at least 3 mm that is parallel to the central hilum

and that does not exhibit substantial mass effect on the hilum. In type III nodes, the cortical thickening is

diffuse and uniform. In type IV nodes, the cortical thickening is diffuse but lobulated. Type III and type IV

nodes are metastatic in 7% and 11% of cases, respectively [5]. Type V and VI nodes exhibit marked

cortical thickening associated with mass effect on the hilum. Type V nodes demonstrate focal eccentric

cortical thickening that displaces the hilum. Type VI nodes appear as round masses with complete

involvement of the node by the thickened cortex, which effaces the hilum. Type V and VI nodes are

metastatic in 29% of cases and 58% to 97% of cases, respectively [5,8]. Type I nodes have no visible

cortex, and type II nodes have a thin hypoechoic cortex measuring under 3 mm; the reader did not

assign these morphologic types given that only indeterminate or suspicious nodes were evaluated.

To assess inter-reader agreement, a second breast imaging radiologist with 19 years of post-

fellowship experience (HC) independently categorized node morphology on US for 38.6% (241/624) of

the cancers; these 241 cancers were selected at random. For 58/624 (9.3%) cases with a discrepancy

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between the two readers, a third breast imaging radiologist (JL) with 21 years of post-fellowship

experience reviewed the US images and provided a classification that was used for purposes of the

study analysis.

Statistics

Patient age was compared between patients with nodal metastases from lobular carcinoma and

ductal carcinoma using the Wilcoxon rank sum test; patients with nodal-metastatic bilateral breast

cancers with discordant histologies were excluded from this analysis. The tumor characteristics

extracted from the EMR were compared between lobular carcinoma and ductal carcinoma using the

Fisher’s exact test or chi-square test. The percentage of cancers for which US detected the nodal

metastases was compared between lobular carcinoma and ductal carcinoma using Fisher’s exact test.

Then, among the metastatic nodes detected by US, the three US characteristics (number, size, and

morphology) assessed at the time of retrospective image review were compared between lobular

carcinoma and ductal carcinoma using Fisher’s exact test or chi-square test. For purposes of analysis,

nodal morphology of the suspicious or abnormal nodes on US was dichotomized as type III or IV versus

type V or VI. These features were also determined for mixed lobular and ductal carcinomas, though the

results for mixed carcinomas did not undergo formal significance testing in comparison with the study’s

two primary histologic groups. For metastatic nodes that were not detected on US, nodal size was

recorded based on surgical pathology and summarized descriptively. For the 241 nodes for which nodal

morphology was assessed independently by the first two radiologists, interreader agreement for

morphology (dichotomized as type III or IV versus type V or VI) was assessed using the percentage

agreement between the two radiologists and the kappa coefficient [9]. All tests were two-sided, and p

values less than .05 were considered statistically significant. Statistical analysis was carried out using R

(version 3.6.3, R Development Core Team).

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Results

Among the 723 patients with axillary nodal metastases, patients with lobular carcinoma were

older than patients with ductal carcinoma (median age of 58 and 52 years, respectively; p <.001). Table 1

summarizes the tumor characteristics at presentation in lobular carcinoma, ductal carcinoma, and

carcinoma with mixed histology, and reports statistical comparisons between the lobular and ductal

carcinoma groups. Lobular carcinoma with nodal metastases was grade 1, 2, and 3 in 28.9%, 57.9%, and

13.2%, respectively, whereas ductal carcinoma with nodal metastases was grade 1, 2, and 3 in 4.6%,

37.7%, and 57.5% (p <.001). Lobular and ductal carcinoma were ER positive in 97.4% and 64.0%,

respectively (p <.001). Lobular and ductal carcinoma were HER2 negative in 94.7% and 75.4%,

respectively (p <.001). The Ki67 proliferation index was low, medium, and high in 43.4%, 42.1%, and

10.5% of lobular carcinomas, versus 12.1%, 21.5%, and 47.1% of ductal carcinomas, respectively (p

<.001). The molecular subtype for lobular carcinoma was luminal A for 26.3%, luminal B for 71.1%, HER2

enriched for 2.6%, and triple negative for 0.0%, whereas for ductal carcinoma was luminal A for 3.4%,

luminal B for 60.2%, HER2 enriched for 10.6%, and triple negative for 25.8% (p <.001). Lobular carcinoma

exhibited a T category of T1 in 25.4%, T2 in 33.3%, and T3 in 41.3%, whereas ductal carcinoma exhibited

a T category of T1 in 22.0%, T2 in 53.1%, and T3 in 23.7% (p =.001). Lobular carcinoma was stage IB in

2.7%, stage II in 16.8%, stage III in 66.7%, and stage IV in 10.5%, whereas ductal carcinoma was stage IB

in 1.5%, stage II in 36.3%, stage III in 48.5%, and stage IV in 13.7% (p =.009). Focality was not statistically

different between lobular and ductal carcinomas (p =.19).

A total of 99 metastatic axillary lymph nodes (15 lobular, 66 ductal, 18 mixed) did not exhibit

indeterminate or suspicious nodes on the pretreatment US. These metastatic nodes were all diagnosed

by surgical sentinel lymph node biopsy and/or subsequent axillary dissection. In the remaining 624

breast cancers with metastatic nodes (61 lobular, 520 ductal, 43 mixed), the metastatic nodes were

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visualized on the pretreatment US and characterized as indeterminate or suspicious and then diagnosed

by percutaneous US-guided FNA. Thus, the pretreatment US detected the metastatic axillary lymph

nodes in 80.3% (61/76) of cancers for invasive lobular carcinoma versus 88.7% (520/586) for invasive

ductal carcinoma (p =.04). Of the 624 breast cancers with metastatic nodes diagnosed by FNA, 516

cancers (52 lobular, 429 ductal, 35 mixed) underwent subsequent surgical biopsy, which confirmed the

nodes as metastatic in all cases. The remaining 108 cancers did not undergo surgical confirmation of the

nodal metastases for the following reasons: 71 were in patients who presented with stage IV disease, 4

were in patients who underwent surgical treatment at a different facility without available pathology, 7

were in patients who were deemed poor surgical candidates, 9 were in patients who died, and 17 were

in patients who were lost to follow up. For lobular carcinoma, of the fifteen nodal metastases that were

not detected on US, surgical pathology demonstrated that five were micrometastases (0.2-2.0 mm), six

measured 2.1-5.0 mm, and four measured 6.0-10.0 mm. Figures 2 and 3 demonstrate imaging findings in

two women with invasive lobular carcinoma and biopsy-proven metastatic axillary lymph nodes that

were not detected on US. Figure 2 also demonstrates the corresponding surgical histopathology. For

ductal carcinoma, of the sixty-six ductal nodal metastases that were not detected on US, surgical

pathology revealed that 27 were micrometastases (0.2-2.0 mm), 24 measured 2.1-5.0 mm, 12

measured 6.0-10.0 mm, and three measured >10.0 mm (specifically 12.0, 13.0 and 20.0 mm).

Among the metastatic nodes detected by US, the retrospective image review identified ≥3

abnormal nodes in 50.8% of lobular carcinoma versus in 69.2% of ductal carcinoma (p =.003). Among the

metastatic nodes detected by US, the size of the largest abnormal lymph node in lobular carcinoma was

≤2.0 cm in 65.6%, 2.1-4.0 cm in 31.1%, and ≥4.1 cm in 3.3%, whereas in ductal carcinoma was ≤2.0 cm in

47.3%, 2.1-4.0 cm in 45.4%, and ≥4.1 cm in 7.3% (p =.03). Among the metastatic nodes detected by US,

the morphology was type III or type IV in 68.9% for lobular carcinoma versus 28.8% for ductal carcinoma

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(p <.001). Figure 4 demonstrates an example a type V metastatic node in a woman with invasive lobular

carcinoma.

The percentage agreement among the 241 cases categorized by two radiologists was 82.2%

(198/241; 95% CI, 0.767-0.868), with kappa coefficient of 0.63 (95% CI, 0.54-0.73).

Discussion

In this study, we compared axillary nodal metastases in patients with invasive lobular carcinoma

and invasive ductal carcinoma. Pretreatment US detected a lower percentage of nodal metastases in

lobular than in ductal carcinoma. In addition, nodal metastases in lobular carcinoma were fewer,

smaller, and less likely to exhibit mass effect on the hilum.

Lobular carcinoma is often considered subtle on imaging [1,3]. Even with digital mammography

technique, the sensitivity for lobular carcinoma may be as low as 70-85% [1,10]. While lobular

carcinoma may manifest as a mass (44-65%), less conspicuous and variable imaging findings such as

architectural distortion (10-34%) or asymmetry (1-14%), possibly seen in only one view, may be the sole

imaging finding [11]. Rare manifestations include calcifications and a shrinking breast appearance,

yielding an asymmetric smaller size of the affected breast [12,13]. Similar to mammography, US also

may show less specific features, such as posterior shadowing (63%) or possible hyperechogenicity (5%)

[14]. Approximately 10% of lobular carcinomas remain occult on US. Because MRI sensitivity is high

(range, 93% to 95%), MRI is a useful adjunct modality for evaluating the primary tumor size and

detecting additional sites of disease [15-17].

Our findings suggest that the biology that accounts for the nonspecific imaging features of

lobular carcinoma in the breast may also apply to nodal metastases from lobular carcinoma. Specifically,

the discohesive infiltrative pattern of spread preserves the nodal architecture. Despite differences in

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grade and other markers of biologic behavior, MRI and PET/CT have been reported to have equivalent

sensitivity in detecting nodal metastases of either histology [18]. However, studies of the sensitivity of

US in detecting nodal metastases have yielded varied results. Some studies report that US-guided FNA

has equivalent sensitivity for nodal metastases regardless of tumor histology [19-21], whereas other

studies report that diagnostic US and/or FNA cytology is less sensitive for nodal metastases from lobular

carcinoma [22-26]. Our present study expands on earlier works by not only comparing the sensitivity of

US for nodal metastases between lobular and ductal carcinoma, but further comparing characteristics of

metastatic nodes between the two groups. Nodal metastases from lobular carcinoma more often show

diffuse cortical thickening, without mass effect on the hilum. The findings support an earlier study that

reported that axillary lymph node FNA is more likely to yield a false-negative result when involvement of

the node is <30% or when the cortical thickness is <3.5 mm [27]. The lower detection rate on US and the

lesser degree of morphologic abnormality for nodal metastases from lobular carcinoma may warrant a

lower threshold for recommending biopsy of an axillary lymph node detected on US, presuming that the

breast cancer histology is known at the time of staging evaluation. If lowering the threshold and

biopsying nodes with a less suspicious appearance on US, then core biopsy may also be considered

(provided that the lymph node is in a location amenable to core biopsy) to provide better node

sampling.

From a pathologic standpoint, the loss of E-cadherin in invasive lobular carcinoma causes tumor

cells to disperse in a “buckshot” pattern or alternatively to align in a single file pattern with minimal

desmoplastic response [28]. The low nuclear grade with fewer mitoses give a bland monotonous

appearance. For nodal metastases, the small size of individual tumor cells may result in more difficult

detection, as there may be no significant mass formation or distortion of the normal nodal architecture.

Cytokeratin immunohistochemistry of axillary lymph nodes has been recommended in patients with

lobular carcinoma to increase the sensitivity for small metastatic deposits [29].

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A limitation of this study is its retrospective single-center design. Also, the nodes detected on US

were diagnosed by FNA. However, subsequent surgical biopsy did not identify a discrepancy in any case.

In addition, because only cancers with biopsy-proven nodal metastases were included, our study is

unable to provide insight into false-positive nodes on US in lobular carcinoma. Further, our statistical

comparisons did not account for the possible effect of intrapatient correlation in those patients with

bilateral breast cancer. Finally, we did not explore any possible impact of lack of detection of nodal

metastases or of morphology of detected nodal metastases on outcomes in lobular carcinoma.

In conclusion, US detects a lower percentage of axillary nodal metastases in lobular carcinoma

than in ductal carcinoma. When US detects nodal metastases in lobular carcinoma, the nodes are fewer

and smaller in comparison with nodal metastases in ductal carcinoma. Further, nodal metastases in

lobular carcinoma more commonly show diffuse cortical thickening and less commonly exhibit mass

effect on the hilum. Given the relatively subtle nature of metastatic nodes in lobular carcinoma

compared with in ductal carcinoma, radiologists should have a lower threshold to recommend biopsy of

axillary lymph nodes detected on US in patients with lobular breast cancer.

Acknowledgments: We thank Kelly Kage, MFA, CMI, for her assistance with the medical graphics in this article.

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22. Upadhyaya VS, Lim GH, Chan EYK, Fook-Chong SMC, Leong LCH. Evaluating the preoperative breast cancer characteristics affecting the accuracy of axillary ultrasound staging. Breast J. 2020 Feb; 26(2):162-167. doi: 10.1111/tbj.13635. 23. Morrow E, Lannigan A, Doughty J, Litherland J, Mansell J, Stallard S, et al. Population-based study of the sensitivity of axillary ultrasound imaging in the preoperative staging of node-positive invasive lobular carcinoma of the breast. Br J Surg. 2018; 105(8):987-995. doi:10.1002/bjs.10791. 24. Kim SY, Kim EK, Moon HJ, Yoon JH, Kim MJ. Is pre-operative axillary staging with ultrasound and ultrasound-guided fine-needle aspiration reliable in invasive lobular carcinoma of the breast? Ultrasound Med Biol. 2016 Jun; 42(6):1263-72. doi: 10.1016/j.ultrasmedbio.2016.01.008. 25. Hackney L, Williams S, Bajwa S, Morley-Davies AJ, Kirby RM, Britton I. Influence of tumor histology on preoperative staging accuracy of breast metastases to the axilla. Breast J. 2013 Jan-Feb; 19(1):49-55. doi: 10.1111/tbj.12042.

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26. Johnson S, Brown S, Porter G, Steel J, Paisley K, Watkins R, et al. Staging primary breast cancer. Are there tumour pathological features that correlate with a false-negative axillary ultrasound? Clin Radiol. 2011 Jun;66(6):497-9. doi: 10.1016/j.crad.2010.11.015. 27. Ewing DE, Layfield LJ, Joshi CL, Travis MD. Determinants of False-Negative Fine-Needle Aspirates of Axillary Lymph Nodes in Women with Breast Cancer: Lymph Node Size, Cortical Thickness and Hilar Fat Retention. Acta Cytol. 2015;59(4):311-4. doi: 10.1159/000440797. 28. Turner RR, Giuliano AE, Hoon DS, Glass EC, Krasne DL. Pathologic examination of sentinel lymph node for breast carcinoma. World J Surg. 2001 Jun;25(6):798-805. doi: 10.1007/s00268-001-0008-5. 29. Cserni G, Bianchi S, Vezzosi V, Peterse H, Sapino A, Arisio R, et al. The value of cytokeratin immunohistochemistry in the evaluation of axillary sentinel lymph nodes in patients with lobular breast carcinoma. J Clin Pathol. 2006 May;59(5):518-22. doi: 10.1136/jcp.2005.029991.

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Table 1. Characteristics of Breast Cancers with Metastatic Lymph Nodes

Characteristic Lobular (n=76)

Ductal (n=586)

Mixed (n=61)

p (Lobular vs Ductal)

Tumor Grade 1 22 (28.9) 27 (4.6) 7 (11.5) <.001 2 44 (57.9) 221 (37.7) 41 (67.2) 3 10 (13.2) 337 (57.5) 13 (21.3) NA 0 (0.0) 1 (0.2) 0 (0.0) ER <.001 + 74 (97.4) 375 (64.0) 57 (93.4) - 2 (2.6) 211 (36.0) 4 (6.6) HER2 <.001 + 4 (5.3) 144 (24.6) 7 (11.5) - 72 (94.7) 442 (75.4) 54 (88.5) Ki67 <.001 Low (<14%) 33 (43.4) 71 (12.1) 18 (29.5) Medium (15%-34%) 32 (42.1) 126 (21.5) 20 (32.8) High (>35%) 8 (10.5) 276 (47.1) 12 (19.7) NA 3 (4.0) 113 (19.3) 11 (18.0) Molecular subtype <.001 Luminal A 20 (26.3) 20 (3.4) 6 (9.8) Luminal B 54 (71.1) 353 (60.2) 51 (83.6) HER2 enriched 2 (2.6) 62 (10.6) 1 (1.6) Triple negative 0 (0.0) 151 (25.8) 3 (4.9) T category .001 T1 (<2.0 cm) 19 (25.4) 129 (22.0) 19(31.1)

T2 (2.1-5.0 cm) 25 (33.3) 311 (53.1) 30(49.2) T3 (≥5.1 cm) 31 (41.3) 139 (23.7) 12(19.7)

Unknown 0 (0.0) 7 (1.2) 0 (0.0) Stage .009 IB 2 (2.7) 9 (1.5) 5 (8.2)

II 15 (16.8) 213 (36.3) 26 (42.6) III 50 (66.7) 284 (48.5) 19 (31.1) IV 8 (10.5) 80 (13.7) 11 (18.0) Unifocal versus multiple sites within breast

0.19

Unifocal 32 (42.7) 302 (51.5) 26 (42.6) Multifocal/multicentric 43 (57.3) 284 (48.5) 35 (57.4)

Data represent number of patients, with percentage in parentheses. ER = estrogen receptor; HER2 = human epidermal growth factor; LN = lymph node; NA = not applicable

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Table 2. Characteristics of Metastatic Axillary Lymph Nodes Detected on Ultrasound Characteristic Lobular

(n=61) Ductal

(n=520) Mixed (n=43)

p (Lobular vs Ductal)

No. of abnormal LNs .003

1 or 2 30 (49.2) 160 (30.8) 20 (46.5)

> 3 31 (50.8) 360 (69.2) 23 (53.5)

Size of most suspicious LN .03

<2.0 cm 40 (65.6) 246 (47.3) 31 (72.1) 2.1-4.0 cm 19 (31.1) 236 (45.4) 12 (27.9)

≥4.1 cm 2 (3.3) 38 (7.3) 0 (0.0) Morphology of most suspicious LN <.001

Type III/IV 42 (68.9) 150 (28.8) 31 (72.1)

Type V/VI 19 (31.1) 370 (71.2) 12 (27.9) Data represent number of patients, with percentage in parentheses. LN = lymph node; NA = not applicable

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Figure 1. Examples of type III through type VI lymph nodes. A, Diagram of type III lymph node, exhibiting diffuse uniform cortical thickening parallel to the hilum. (Reprinted from Chung H, Le-Petross HTC, Leung JWT, Imaging updates to breast cancer lymph node management, RadioGraphics 2021 [in press], with permission of the Radiological Society of North America)B, Type III metastatic axillary lymph node on ultrasound (US) in a72-year-old woman with invasive lobular carcinoma. Dif-fuse uniform cortical thickening is indicated by dashed arrows.C, Diagram of type IV lymph node, exhibiting diffuse lobulated cortical thickening parallel to the hilum. (Reprinted from Chung H, Le-Petross HTC, Leung JWT, Imaging updates to breast cancer lymph node management, RadioGraphics 2021 [in press], with permission of the Radiological Society of North America)D, Type IV metastatic axillary lymph node on US in a 82-year-old woman with invasive lobular carcinoma. Diffuse lobulated cortical thickening is indicated by dashed arrows.E, Diagram of type V lymph node, exhibiting marked cortical thickening with mass effect and displacement of the hilum. (Reprinted from Chung H, Le-Petross HTC, Leung JWT, Imaging updates to breast cancer lymph node management, Radio-Graphics 2021 [in press], with permission of the Radiological Society of North America)F, Type V metastatic axillary lymph node on US in a 51-year-old woman with human epidermal growth factor enriched invasive ductal carcinoma. Displaced hilum is indicated by dashed arrow.G, Diagram of type VI lymph node, manifesting as a hypoechoic mass with complete tumor involvement of the node, with-out a visible hilum. (Reprinted from Chung H, Le-Petross HTC, Leung JWT, Imaging updates to breast cancer lymph node management, RadioGraphics 2021 [in press], with permission of the Radiological Society of North America)H, Type VI metastatic axillary lymph node on US in a 62-year-old woman with invasive ductal carcinoma. No hilum is visible.

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Figure 2. 69-year-old woman with axillary nodal metastases due to grade 2 invasive lobular carcinoma, not detected on pretreatment staging ultrasound.

A, Ultrasound images of four different axillary lymph nodes (circles) demonstrate fatty hila and benign-appearing cortices without thickening. No ultrasound-guided biopsy was performed. At surgical staging of the axilla 3 weeks later, sentinel lymph node biopsy followed by axillary dissection detected six metastatic axillary nodes. One metastatic sentinel lymph node measured 7.0 mm. Axillary dissection detected five additional metastatic nodes, measuring up to 10.0 mm.

B, Photomicrograph (H & E, magnification X 40) demonstrating nodal metastasis from lobular carcinoma, infiltrating and expanding lymph node sinus (arrow).

C, Photomicrograph (H & E, magnification X 100) demonstrating discohesive tumor cells (arrows) present within the lymph node sinus, without loss of architecture. Lymphocytes are present outside of the sinus (circle).

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Figure 3. 53-year-old woman with axillary nodal metastases due to grade 1 invasive lobular carcinoma, not detected on staging ultrasound. No ultrasound-guided biopsy was performed. At surgical staging of the axilla 6 weeks later, sentinel lymph node biopsy followed by axillary dissection detected four metastatic axillary nodes. Two metastatic sentinel nodes measured 3.0 and 7.0 mm. Axillary dissection two additional metastatic nodes, measuring 1.5 mm and 2.0 mm.

A, Bilateral mediolateral oblique digital mammograms demonstrate symmetric axillary lymph nodes (circles).

B, Ultrasound shows three different axillary lymph nodes (circles) with fatty hila and benign-appearing thin or impercepti-ble cortices.

BA

Figure 4. 67-year-old woman with axillary nodal metastases due to grade 2 inva-sive lobular carcinoma.

Ultrasound of the metastatic left axillary node shows marked cortical thickening with a displaced hilum (dotted horizontal arrow), consistent with a type V node.

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Axillary Nodal Metastases in Invasive Lobular Carcinoma Versus Invasive Ductal Carcinoma: Comparison of Node Detection and Morphology by Ultrasound Type of Article : Original Research

Hannah L. Chung, MD The University of Texas MD Anderson Cancer Center Department of Breast Imaging 1515 Holcombe Blvd, Unit 1350, CPB5.3201 Houston Texas 77030 Phone: 713-745-4555 HLChung@mdanderson.org @drhannahchung Hilda H. Tso, DO The University of Texas MD Anderson Cancer Center Department of Breast Imaging 1515 Holcombe Blvd, Unit 1350, CPB5.3201 Houston Texas 77030 Phone: 713-745-4555 HTSo@mdanderson.org Lavinia P. Middleton, MD The University of Texas MD Anderson Cancer Center Department of Anatomical Pathology 1515 Holcombe Blvd Houston Texas 77030 Phone: 713-745-0128 LPMiddleton@mdanderson.org

Jia Sun, PhD The University of Texas MD Anderson Cancer Center Department of Biostatistics 1400 Pressler Street, FCT4.6000 Houston, TX 77030 Phone: 713-792-3452 JSun9@mdanderson.org Jessica W.T. Leung, MD The University of Texas MD Anderson Cancer Center Department of Breast Imaging 1515 Holcombe Blvd, Unit 1350 Houston, Texas 77030 Phone: 713-745-4555 JWLeung@mdanderson.org @DrJessicaLeung

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Corresponding author: Hannah L. Chung, MD

The University of Texas MD Anderson Cancer Center Department of Breast Imaging 1515 Holcombe Blvd, Unit 1350, CPB5.3201 Houston Texas 77030 Phone: 713-745-4555 HLChung@mdanderson.org

Disclosures: JWT serves on the advisory board of Subtle Medical and has been a speaker of GE Healthcare and of Fujifilm.

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