Mammographic detection and staging of invasive lobular carcinoma

Journal of Clinical Imaging 30 (2006) 94 – 98

Mammographic detection and staging of invasive lobular carcinoma Jeroen Veltmana,4, C. Boetesa, L. van Diea, P. Bultb, J.G. Blickmana, J.O. Barentsza a

Department of Radiology, UMC St Radboud, Nijmegen, The Netherlands Department of Pathology, UMC St Radboud, Nijmegen, The Netherlands

b

Received 10 August 2005; received in revised form 13 September 2005; accepted 13 September 2005

Abstract The aim of the study was to evaluate mammography in detecting and staging of invasive lobular carcinoma (ILC) in order to assess the performance and impact of observer variability. Forty-two cases of ILC were retrospectively evaluated twice by two breast radiologists. Mammographic performance as well as intra- and interobserver variations was evaluated. Thirty-five percent to 37% of the cases were understaged. The largest differences between radiologists were found in the breast imaging reporting and data system (BIRADS) classification and staging performance. These results can have serious influence on patient management. D 2006 Elsevier Inc. All rights reserved. Keywords: Breast; Cancer; Mammography; Lobular

1. Introduction Invasive lobular carcinoma (ILC) is a challenge for mammography. Although ILC represents only about 10% of all breast tumors [1], it is known to be one of the most important reasons for a false-negative mammogram [2]. The diffuse infiltrating growth pattern where normal tissue is infiltrated by strands of malignant cells, often with scarce fibrotic reaction, is one of the reasons why ILC is difficult to detect [2]. In addition, if an ILC produces a mammographic detectable lesion, it is often (85%) of relatively low or equal radiographic opacity compared to normal fibroglandular tissue [1]. Even lesions as large as 50 mm can still be occult on mammography [3]. Mammographic sensitivity for ILC varies between 57% and 89% [2,4–6]. Krecke and Gisvold [2] found no evidence of a malignant tumor on mammography even in retrospect in 16 of 184 cases.

4 Corresponding author. 430 Department of Radiology, UMC St Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: +31 24 361 45 45; fax: +31 24 354 08 66. E-mail address: [email protected] (J. Veltman). 0899-7071/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.clinimag.2005.09.021

The infiltrative growth pattern of ILC also results in size underestimation of mammography compared to histopathological evaluation [7,8]. For adequate treatment, accurate tumor staging is of great importance [9]. Because ILC is difficult to detect on mammography and tumor staging is of great importance for the treatment of breast cancer patients, we evaluated the mammographic detection and staging of ILC using two observers in order to assess its performance and the impact of observer variability.

2. Materials and methods Using a pathology database (PALGA), we selected surgically treated patients with pure ILC in the period from January 2000 until December 2004. A total of 42 patients, mean age 64 years (range 44–85 years), were included in the study. Mammographic examinations were performed using a Siemens Mammomat 3000 or General Electric DMR mammographer. Each patient underwent mammography in the oblique and craniocaudal direction. If a suspicious area was seen, additional magnification spot films were made.

J. Veltman et al. / Journal of Clinical Imaging 30 (2006) 94 – 98

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Table 1 Mammographic tumor characteristics Radiologist 1 Lesion type

Lesion subtype

Mass Shape

Delineation

Density

Round Oval Lobular Irregular Sharp Lobulated Obscured Vague Spiculated High Equal Low Radiolucent

Calcification Lightly suspect for malignancy Highly suspect for malignancy Architectural distortion

All examinations were retrospectively evaluated twice by two experienced breast radiologists, further referred to as sessions A and B and radiologists 1 and 2. Both radiologists have over 10 years of experience in mammography in both a screening and a clinical setting. For blinding purposes, the mammograms were mixed twice into a stack of approximately 250 other mammograms containing both other types of malignancies and negative cases. Detection, aspect of the lesion (mass, calcifications, or architectural distortion), lesion density compared to breast tissue, lesion size, and breast imaging reporting and data system (BIRADS) classification [10] were scored. Lesions interpreted as benign were not scored. The size of the tumor was measured by determining the longest axis through the displayed lesion as if the measurement was done for clinical purposes. Whether a lesion was palpable was not known to the radiologist at the time of evaluation; therefore, this information was not included in this study. Patients underwent either a mastectomy or a breast-saving surgical excision. None of the patients received preoperative systemic treatment. Specimens were examined using a correlative radiologic–histologic mapping technique [11]. All measurements were translated into tumor stage according to the TNM classification [12]. For inter- and intra-observer evaluation, the j value was calculated between both sessions per observer and between sessions A and B for every observer for tumor stage and BIRADS classification. For the relative strength of agreement associated with the various values of j, the nomenclature by Landis and Koch [13] was used: slight agreement for 0bjb0.20; fair agreement for 0.20bjb0.40; moderate agreement for 0.40bjb0.60; substantial agreement for 0.60bjb0.80; and almost perfect agreement for 0.80bjb1.0.

Radiologist 2

Session A

Session B

Session A

Session B

30 2 3 – 25 1 – 2 12 15 5 25 – – 1 – 1 10

30 1 4 1 24 1 1 1 14 13 10 20 – – 2 1 1 7

32 6 2 1 23 3 – – 5 24 8 21 3 – 2 2 – 4

30 3 5 1 21 5 – – 7 18 12 14 4 – 1 1 – 6

3. Results Twenty-six tumors were located in the left breast; 16 in the right. Twenty-seven patients underwent a mastectomy; 15 breast-saving surgery. Mean tumor size at pathological examination was 33 mm (range 3–110 mm). Based on pathological measurements, 20 patients had a T1; 13, a T2; and 9, a T3 tumor. Radiologist 1 detected 41 and 39 lesions in sessions A and B, respectively; radiologist 2, 38 and 37. In a case-to-case comparison, radiologist 1 differed in four (10%) patients between sessions A and B for tumor detection; for radiologist 2 this was in one case (2%). Between the radiologists, there

Fig. 1. Craniocaudal (A) and oblique mammogram (B) of a 48-year-old woman with ILC. In this patient, both radiologists detected a retromammillare, irregular-shaped mass located in the left breast (arrow) with calcifications as associated finding of about 15 mm. Pathology found an ILC of 19 mm.

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Table 2 Staging results

4. Discussion Radiologist 1

Radiologist 2

Tumor stage

Pathology

Session A

Session B

Session A

Session B

T0 T1 T2 T3

– 20 13 9

1 27 11 1

3 29 8 2

4 24 11 3

5 28 7 2

was disagreement in five (12%) and two (5%) cases comparing results from sessions A and B. All lesions were detected if the results of both radiologists and both sessions were combined. Both radiologists described most lesions as an irregular-shaped mass with equal density compared to breast tissue (Table 1). An example is displayed in Fig. 1. Compared to the pathological findings, radiologist 1 staged 60% correct, overstaged 3%, and understaged 37% in session A. In session B, these percentages were similar. Radiologist 2 scored 60%, 5%, and 35% in session A, respectively, and 52%, 0%, and 48% in session B, respectively. Staging results are presented in Table 2. For tumor staging, radiologist 1 differed in seven (17%) patients between the two sessions; radiologist 2 in nine (21%) patients. Comparing the results of both radiologists resulted in 12 (29%) and 9 (21%) differences for sessions A and B, respectively. The intra-observer variation for staging was j=0.66 and j=0.70, respectively, for both radiologists. The j value for interobserver agreement was 0.46 and 0.65 comparing sessions A and B, respectively. In seven patients (17%), multiple lesions were reported by either of the radiologists in any of the sessions. In one of these cases, the multiple lesions were pathologically confirmed. The pathologist also found multiple, clearly separated, lesions in six other patients not described on mammography. In the BIRADS classifications, radiologist 1 differed in 11 (26%) patients between the two sessions; radiologist 2 in 9 (21%) patients. Comparing the results of both radiologists from sessions A and B resulted in 12 (29%) and 13 (31%) differences, respectively. BIRADS classification results are presented in Table 3. For the BIRADS classification, the j value for intraobserver variation was 0.42 and 0.68 for radiologists 1 and 2, respectively. Interobserver agreement was j=0.45 and j=0.50 comparing the BIRADS classification for sessions A and B, respectively.

The reason for performing a mammogram is to screen for or to evaluate clinically detected breast lesions. Invasive lobular carcinoma is one of the most important reasons for false-negative mammograms; up to 19% can be missed on mammography [2,4]. In our study, between 2% and 12% of ILC was not detected. The higher detection rate is most likely a result of the retrospective setting, with higher incidence of abnormal mammograms when compared to general screening, in which the mammograms were evaluated. Nonetheless, the maximal difference between radiologists in detecting ILC was 12%; the difference between both sessions of the same radiologist was up to 10%. Because all lesions were detected when combining all evaluations, the difference in detection rate was based on the interpretation of the mammograms and not on the visibility of the lesions. In the lesion characteristics, the most evident difference between observers can be found in architectural distortions (Table 1). Three and four of the lesions missed by radiologist 2 in sessions A and B, respectively, were described by radiologist 1 as an architectural distortion (Fig. 2). All three lesions missed by radiologist 1 in session B were described in session A as an architectural distortion by the same radiologist. Architectural distortions are more subtle to detect on mammography. Subtle mammographic signs, like architectural distortion and asymmetric density, are more common in ILC than in other malignancies [2,8]. The observer variability for BIRADS classification showed only moderate agreement in most comparisons. Radiologist 2 managed to obtain substantial agreement between both sessions. If a lesion is detected, the impact for the patient lies mainly in the decision to classify a lesion as BIRADS 3 and not as BIRADS 4 or 5. Classifying an invasive tumor as BIRADS 3 will delay treatment. In our group, five mammograms were classified as BIRADS 3 in one or

Table 3 BIRADS classification results BIRADS classification 1 3 4 5

Radiologist 1

Radiologist 2

Session A

Session B

Session A

Session B

1 1 31 9

3 – 38 11

4 4 21 13

5 4 17 16

Fig. 2. Craniocaudal (A) and oblique mammogram (B) of a 56-year-old woman with ILC. In this patient, radiologist 1 detected an architectural distortion in the upper lateral quadrant of the left breast (arrow). Radiologist 2 evaluated this mammogram as normal. Pathology confirmed a 28-mm large ILC.

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several sessions, resulting in a treatment delay for the patient. A delay of 6 months can already result in a larger tumor size and an increased risk of lymph node metastases [14]. For adequate treatment, accurate breast tumor staging is essential. Variations in staging have a direct influence on treatment. In our study, the tumor was underestimated by mammography in 35% to 48% of the cases. The understaging of ILC on mammography is known in literature [7,15]. Understaging can have a direct influence on patient treatment. Not only can it result in nonradical surgery, but, with larger tumors, the method of staging the axilla can also differ. The false-negative rate of the sentinel node procedure for axilla staging has proven in T1 and T2 to be reliable and to falsely stage b4% of the cases [16]. However, in larger tumors or with multifocality, the procedure has proven to be less ideal [17], making complete axillary lymph node dissection more preferable. Intra-observer agreement was found to be substantial for tumor staging; for interobserver agreement, however, there was only moderate agreement in one session. Disagreement between observers can both negatively and positively contribute to the accuracy of tumor staging. Combining all evaluations, 52% of all ILC cases would have been understaged in the worst case; 21% at best. Although the observer agreement was found to be substantial in three out of four comparisons, the difference between worst and best case scenario’s indicates that the impact of observer disagreement in tumor staging can also be substantial. Besides primary tumor staging, multifocality or multicentricity needs to be detected for radical surgery to be possible. In ILC, multifocality is more common than in invasive ductal carcinoma [18]. In our study, mammography was not adequate in detecting multifocal or multicentric lesions. Not detecting multiple foci of ILC on mammography has been described in the literature [19,20]. However, this has also been described for mammography in other types of breast cancer [21–23]. Multifocality is one of the main reasons for disease recurrence [24]. The limitations found using mammography may be overcome using other imaging modalities like ultrasound or magnetic resonance imaging (MRI). In the literature, the sensitivity for ultrasound for the detection of known ILC varies between 68% and 97% [5,15,19,25–27]. However, like mammography, ultrasound tends to underestimate tumor size [15,28]. This does not make ultrasound a useful adjunct in overcoming the limitations of mammography. Magnetic resonance imaging has proven to be highly sensitive for the detection of invasive breast carcinoma [19,29]. This has also been proven for ILC specifically [15,19,30]. Invasive lobular carcinoma, however, can be difficult to detect on MRI in some cases. The main reason for this is the diffuse single-strand growth pattern that does not create significant neovascularity to give enough contrast enhancement [31]. For measuring the extent of disease, MRI has proven to be more accurate than mammography [19,21]. Additional multifocal or multicentric lesions in the breast are

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also better detected using MRI [32,33]. Therefore, the use of MRI in the preoperative staging of ILC has the potential to overcome the limitations of mammography. Differences between radiologists proved to be responsible for the nondetection of ILCs on mammography or treatment delay. The understaging of ILC by mammography can have a serious influence on the clinical management of patients with ILC. Therefore, we conclude that mammography alone is not enough in detecting and especially in the staging of ILC. Better modalities, like MRI, should be used if available, at least for staging of ILC.

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