Breast-conserving therapy followed by radiation therapy and chemotherapy is the treatment of choice for early stage breast carcinoma. Negative margin status has become a prerequisite for breast conservation therapy, rec- ognizing that positive margins impact negatively on local recurrence rates. Residual disease following initial attempt at breast conservation is estimated to be between up to 70%.1 Even with accurate preoperative needle localiza- tion, the negative margin rate is high because there is often incomplete knowledge of the true extent of the tumor before the operation, despite our best attempts with phys- ical examination, magnification mammography, and ultra- sound. Gwin and colleagues2 demonstrated that 45% of women undergoing re-excision had residual tumor and that the majority (62%) had residual invasive carcinoma.
This is the basis for re-excision in the patient with ques- tionable or inadequate margin status.
Re-excision or mastectomy is performed when initial margins of resection are positive or close for tumor. The extent of margin positivity correlates with risk of residual tumor and recurrent disease. Schnitt and colleagues3noted the relationship between microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast-conserving surgery and radia- tion therapy. No recurrences were found at a minimum of 5-year follow up in patients with negative margins, 4%
recurrence rate with close margins (<1mm), 6% recur- rence with focally positive margins (⭓3 high power fields), and 21% with more than focally positive margins. Addi- tional factors such as young patient age and extensive intraductal component (EIC) have been associated with a higher risk of recurrence.4 Further, when initial margins are positive, younger women have been shown in one series to be more likely to have residual tumor at re- excision despite radiation therapy.5,6
It is known in the pathology literature that unifocal car- cinoma diagnosed on mammography and clinical exami- nation can have residual disease following surgery not only at the lumpectomy site but also in a separate quadrant.
Holland and colleagues7have examined mastectomy spec- imens for clinically and mammographically suspected uni- focal disease and found that 37% of women have no additional disease, 20% have disease within 2 cm of the lumpectomy site, 43% had disease greater than 2 cm away from the lumpectomy site, and 7% had disease greater than 4 cm away from the lumpectomy site. Difficult histologies, such as invasive lobular carcinoma and EIC tumors, are notoriously difficult to predict tumor extent and are more likely to have associated positive margins (Figure 13.1). But unsuspected residual disease can occur with all breast cancer histologies (Figure 13.2).
1. The Preoperative Work-Up
The traditional work-up of suspect lesions involves mam- mography and ultrasound, even though there is compelling data in some specific cases that MRI may add significant information (Figure 13.3). The preoperative extent of disease is better assessed with magnetic resonance imaging (MRI) than with conventional imaging such as mammog- raphy and ultrasound in multiple studies.8This is particu- larly true with specific tumor histology of invasive lobular carcinoma9but also applies to invasive ductal carcinoma, which is much more prevalent. In addition to invasive car- cinomas, there is emerging data that MRI may also better stage patients who are diagnosed preoperatively with pre- invasive ductal carcinoma in situ (DCIS)10(Figure 13.4).
2. Relationship Between Residual and Recurrent Disease
Residual disease following lumpectomy is not the same as recurrence. However, there is a distinct relationship between these two entities. Residual carcinoma is sus- pected when the initial attempt at surgical resection is incomplete (Figure 13.5). Pathologic analysis of the
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Assessment of Residual Disease
Elizabeth A. Morris
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Figure 13.1. Residual invasive lobular carcinoma (thin arrow) posterior to the lumpectomy site (thick arrow). This and all fol- lowing examinations are performed several weeks following initial lumpectomy. Images are performed on a 1.5 Tesla (T) system using a fat-suppressed three-dimensional (3D) fast spoiled gradient echo (FSPGR) sequence in the sagittal plane unless otherwise indicated.
Figure 13.2. Two patients with positive margins. (A) Residual invasive ductal carcinoma posterior to the seroma cavity. (B) Residual DCIS anterior to the seroma cavity.
A B
216 E.A. Morris
Figure 13.3. (A) Biopsy proven invasive ductal carcinoma (arrow) was identified on mammography but is much larger on MRI (arrow). (B) What was not appreciated on mammography was the extensive intraductal component (EIC) seen on this image.
Figure 13.4. (A) Magnification mammography demonstrates a small 4-mm cluster of calcifications that were biopsied yielding DCIS.
(B) Preoperative staging MRI demonstrates more extensive DCIS involving an entire segment.
A B
A B
lumpectomy specimen and the inked surgical margins may indicate that the carcinoma is at or close to the margins of resection. Specimen radiography is useful to determine lesion retrieval.11If the initial carcinoma contained calcifi- cation, then magnification mammography can be per- formed to assess whether residual suspicious calcifications are remaining.12 If present, these can be localized under mammographic guidance, which, it is to be hoped, can direct the surgeon to area of residual disease. Problems arise if the original tumor did not contain calcifications.
Radiographically, the ability to detect residual masses at the lumpectomy site is limited as postoperative distortion obscures evaluation for residual masses.13 (Figure 13.6).
Additionally, if the in situ component is not associated with calcifications, then assessment of residual disease is very limited (Figure 13.7). In these cases the surgeon usually returns to the operating room and blindly excises the edge of the lumpectomy cavity.
There is strong emerging evidence that breast MRI can offer important information regarding the presence of residual carcinoma14(Figure 13.8), particularly in difficult histologies such as invasive lobular carcinoma and carci- nomas associated with an extensive intraductal component (Figure 13.9). Additionally, in patients with difficult- to-evaluate dense breasts there may be a role for MRI following resection with positive or close margins (Figure 13.10). Carcinomas without associated calcifications may also benefit from the use of MRI if margins are close or positive (Figure 13.11).
Figure 13.6. (A) Postoperative mammogram limited due to breast density and distortion; no suspicious findings are identi- fied. (B) MRI demonstrated seroma cavity (thin arrow) and large Figure 13.5. Residual invasive lobular carcinoma adjacent to seroma cavity (not shown).
residual mass posterior to the seroma cavity (thick arrow) that represented residual invasive ductal carcinoma.
A
B
218 E.A. Morris
Figure 13.7. (A) Postoperative mammography performed for positive margins in a patient with invasive ductal carcinoma and associated DCIS. The original tumor had no associated calcifica-
tions. Posterior biopsy cavity identified associated with clips. (B) Postoperative MRI demonstrated residual foci of uncalcified DCIS surrounding the biopsy cavity.
Figure 13.8. (A) Residual invasive ductal carcinoma (thin arrow) in same quadrant as lumpectomy site (thick arrow).
Patient was treated with needle localization and re-excision with
ultimately negative margins. (B) Residual DCIS in multiple quadrants from the lumpectomy site (not shown) necessitating mastectomy.
A B
A B
Figure 13.8. (Continued) (C) Invasive lobular carcinoma with positive margins. Nodular enhancement along the anterior seroma cavity represented residual invasive disease. Contrast this to thin enhancement along the posterior cavity where no resid- ual disease found at surgery. Note that MRI cannot diagnose residual microscopic disease as the granulation tissue at the
margin will enhance. (D) Residual invasive ductal carcinoma (arrow) in the same quadrant (multifocal) as the initial lumpec- tomy. Although the patient had positive margins, no residual disease was found at the lumpectomy site (seen with thin rim enhancement). Patient received breast conservation.
Figure 13.9. (A) Residual invasive lobular carcinoma (arrows) posterior to seroma cavity. (B) Residual DCIS in a patient with EIC (lumpectomy site not imaged on this section).
C D
A B
220 E.A. Morris
Figure 13.10. (A) Clumped enhancement anterior to the lumpectomy site in the upper outer quadrant in a patient with extremely dense breasts represents residual DCIS. (B) Post-
operative seroma (arrow) in a heterogeneously dense breast does not disclose any suspicious abnormalities. At re-excision no residual disease was found.
Figure 13.11. (A) Residual mass in same quadrant as lumpec- tomy (arrow) performed for DCIS with positive margins.
Directed ultrasound demonstrated a hypoechoic mass that was biopsied percutaneously yielding invasive ductal carcinoma. The patient elected to undergo mastectomy. (B) Residual linear
clumped enhancement represented residual DCIS anterior to the lumpectomy site (arrow). No calcifications were noted on post- operative magnification mammography. Note enhancing scar extending from skin to site of surgery.
A B
A B
The role of MRI in the case of close or positive margins is to evaluate for the presence of bulky residual disease (Figure 13.12). Residual microscopic disease at the surgi- cal margin will not be well evaluated with MRI; however, this is likely not the role of MRI in the immediate post- operative patient (Figure 13.13). Uniformly, if the patient has close or positive margins the surgeon will re-excise the seroma cavity margin. Microscopic residual disease will usually be successfully excised with the re-excision, regard- less of the imaging results. The role of MRI, therefore, is in the assessment of bulky residual disease at the margin of resection that can direct the surgeon to a particular margin and the assessment of residual disease distant from the lumpectomy site that would indicate the patient be best served by mastectomy (Figure 13.14).
Recurrence occurs in a treated breast following lumpec- tomy (with negative margins) and usually chemotherapy and radiation therapy (Figure 13.15). It occurs after treat- ment has been initiated or terminated and is thought to be either due to undetected tumor that was not adequately treated at the time of detection of the index tumor or due to de novo development of cancer. Recurrence may develop despite the presence of negative margins at the time of surgery and despite the administration of whole
breast radiation. The undetected carcinoma that causes recurrence likely is residual multifocal or multicentric tumor that is not detected by means of conventional imaging at the time of diagnosis. Rates of recurrence vary and are increased in patients with positive margins, in young patients, and in tumors with an extensive intraduc- tal component.
The clinical experience with recurrence occurred in the days before the use of breast MRI for preoperative staging.
There is some hope that by using preoperative breast MRI the incidence of recurrence can be decreased. Breast MRI has been shown to detect 13% to 33% more disease pre- operatively than mammography.15–17Therefore, it would be assumed that breast MRI in the preoperative setting is detecting some of the undetected yet present tumor at the time of surgery that is unsuspected by the treating physi- cians. However, a discrepancy arises, as the recurrence rate (1%–2% per year) is not identical to the undetected disease rate shown with MRI (13%–33%). This is likely due to the fact that the chemotherapy and/or radiation therapy directed to the breast are extremely efficacious and that some, if not the majority, of this residual disease is successfully treated. At this writing, disease that is susceptible to treatment by additional therapy such as Figure 13.12. (A) Bulky residual disease anterior to the lumpec-
tomy site. (B) Postoperative seroma without evidence of bulky disease. Margins enhance irregularly though uniformly. On the
basis of the MRI findings, small microscopic disease cannot be excluded.
A B
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Figure 13.13. (A) Postoperative seroma demonstrates clip arti- fact and thin enhancement around the cavity due to granulation tissue. No nodules or masses or asymmetric areas of enhance- ment are identified to suggest residual disease. Pathologically, no
residual was found on re-excision. (B) False-negative MRI. Post- operative seroma with tiny focus (2 mm) of DCIS at re-excision.
Small foci of residual disease may not be seen with MRI. A neg- ative MRI does not preclude re-excision.
Figure 13.14. (A) Additional clumped enhancement represent- ing DCIS in a separate quadrant from the lumpectomy site (arrow). Patient received mastectomy. (B) Several months fol- lowing lumpectomy patient presents for radiation. Surgery per- formed for mammographic calcifications elsewhere yielded DCIS with close margins. Magnetic resonance imaging performed to
evaluate adequate excision. Lumpectomy site is demonstrated by clips (arrow). Note the postoperative seroma has resolved. An irregular heterogeneously enhancing mass is seen posteriorly in the breast and was biopsied yielding invasive ductal carcinoma.
The patient subsequently received mastectomy.
A B
A B
Figure 13.15. One year following breast-conserving therapy for invasive ductal carcinoma followed by chemotherapy and radia- tion, a patient presents with fullness at her lumpectomy site.
Mammography was unrevealing and on ultrasound there was a suggestion of a mass. Magnetic resonance imaging performed to evaluate for possible recurrence. (A) On MRI the lumpectomy site is marked by clips causing artifact (arrow). In the breast there are two irregular heterogeneously enhancing masses that repre-
sent recurrence. (B) MRI perfomed in a patient as a baseline following treatment with chemotherapy and radiation therapy.
Margins were negative. Lumpectomy site demonstrates clip arti- fact (arrow) and associated clumped enhancement as well as (C) additional small masses in a separate quadrant, all of which represented DCIS with invasion. The patient underwent mastectomy.
A B
C
chemotherapy and radiation therapy is unable to be dif- ferentiated from disease that is resistant to treatment. It may be useful in the future to use MRI to identify those patients in whom adjuvant radiation may not be helpful as the course of radiation is not without associated morbid- ity, not to mention cost and time savings.
3. Pathology Issues
Breast cancer growth is not always predictable and not always in the same pattern. Certain histologies have classic growth patterns, but in general all breast histologies can demonstrate overlapping appearances, particularly on MRI. Similarly, overlapping kinetic parameters are also seen. However, preoperative MRI may give an indication whether the tumor is truly unifocal, multifocal, or multi- centric. In general, invasive ductal carcinomas generally present as a mass and can be entirely removed at surgery.
However, if the tumor is associated with satellite lesions representing multifocal disease or if it is associated with an extensive intraductal component, then the likelihood of positive margins increases significantly. Invasive lobular carcinomas are notoriously difficult to detect and have a specific characteristic growth pattern of single file growth, allowing the tumor to attain a large overall size without amassing great cellular density so that even large tumors in fatty or mildly dense breasts are difficult to perceive.
Ductal carcinoma in situ is perhaps the easier of all to detect because it can manifest as calcifications and can be detected on mammography. The problem arises that not all DCIS is calcified and even significant grades of DCIS may not produce necrosis and, therefore, calcifications may be absent and the tumor may evade detection on the mam- mogram. Use of preoperative MRI in these patients may also significantly impact the presence of residual DCIS.
When localizing nonpalpable lesions for surgical removal, it is known that despite efforts to bracket lesions and add additional wires under mammographic or ultra- sound guidance, the chance for complete surgical removal is not altered and the chance of obtaining negative margins is not increased.18Therefore, despite our best attempts at defining tumor extent with conventional imaging, we are not always successful. It remains to be seen whether local- ization under MRI can achieve an improved negative margin rate.
4. Postoperative Work–Up
Mammographic assessment is currently the gold standard for preoperative assessment of disease extent and for the postoperative assessment of residual disease and has been discussed previously. Coned magnification views are helpful in detecting additional suspicious calcifications
before surgery to plan for adequate excision and are useful for detecting residual calcifications after surgery. The pres- ence of residual calcifications regardless of morphology is highly predictive of residual disease.12 Residual masses, suspicious for residual invasive carcinoma, however, are much less well assessed on mammography, as there has been a surgical procedure in the area with a postoperative hematoma/seroma that can easily obscure a residual mass.
Ultrasound assessment after surgery is not helpful for calcifications and therefore residual DCIS is not reliably detected. However, assessment by ultrasound may be valu- able if there is a high suspicion for a residual mass and may be a follow-up test if the mammogram result is negative.
Additionally, there is some evidence that postoperative ultrasound may be extremely helpful in assessing residual masses away from the lumpectomy site.19
Out of the modalities discussed so far, MRI has the clear advantage in the detection of residual disease following initial attempt at lumpectomy when close or positive margins are found. By virtue of the fact that MRI uses intravenous contrast and assesses areas of vascularity, sig- nificant residual disease can be reliably assessed.
One of the areas where MRI is not particularly helpful is directly at the margin of resection where there is normal granulation tissue that enhances due to the increased angiogenesis. Therefore, the strength of MRI is not at the margin of lumpectomy site for small microscopic disease.
Magnetic resonance imaging is good at suggesting asym- metric residual bulky disease directly at the lumpectomy site. Magnetic resonance imaging is best used in the detec- tion of residual disease at a distance from the lumpectomy site that was not suspected preoperatively.
5. Magnetic Resonance Imaging Experience
Orel and colleagues20 evaluated postoperative patients with MRI to assess for residual disease and found a posi- tive predictive value (PPV) of 82% and negative predic- tive value (NPV) of 61%. False-positive enhancement at the biopsy site was seen. In a study conducted by Hwang and colleagues10with 51 patients diagnosed with DCIS, it was found that MRI had an accuracy of 88% in predicting residual disease, 82% in predicting invasive disease, and 90% at predicting multicentricity. From this study the detection of additional disease that impacts on the patient’s management (multicentricity) was the strength of MRI. A prior study from the same institution investigated the optimal timing between surgery and the performance of MRI.14Based on the analysis of 68 patients at varying days following surgery, it was found that the best time to image was approximately 1 month following surgery.
Although it is very likely that the false-negative areas of
224 E.A. Morris
enhancement are less the longer one waits after initial surgery, the trade-off is prolonging definitive surgical treat- ment for the patient. It is doubtful that most patients will elect to wait for the MRI for a modest benefit in PPV and NPV.
In a study at Memorial Sloan-Kettering Cancer Center (MSKCC), we evaluated 100 patients with positive or close margins following initial attempt at breast conservation.
All patients were potential candidates for breast conser- vation before MRI. Lesions on MRI were classified as multicentric (different quadrant than operative site), multifocal (same quadrant, >2cm away from operative site), and unifocal (within 2 cm of operative site). All patients underwent definitive surgery. Fifty-eight patients had residual disease at surgery: 20 multicentric, 15 multi- focal, and 23 unifocal. Magnetic resonance imaging identi- fied 18 of 20 (90%) cases of multicentric, 14 of 15 (93%) cases of multifocal, and 18 of 23 (78%) cases of unifocal residual disease. There were 13 false-positive findings, including 5 cases of high-risk lesions [lobular carcinoma in situ (LCIS), atypia], 6 suspicious lesions at the lumpectomy site, and 2 lesions elsewhere in the breast. Eight false-neg- ative findings included two cases of multicentric DCIS occult to MRI and six cases of residual disease (four inva- sive and two microscopic DCIS) immediately at or near the lumpectomy site. Overall PPV was 82% and NPV was 84%. Magnetic resonance imaging was most successful at identifying unsuspected multicentric and multifocal disease.
6. Goals of Breast Cancer Treatment
Clearly, the goal in breast cancer treatment is the surgical removal of all foci of carcinoma. In addition to surgical removal, traditional treatment involves the administration of whole breast radiation and boost radiation to the lumpectomy site in the thought that there are undetected residual islands of tumor that have not been removed sur- gically and can benefit from treatment by external beam radiation. With improvements in the ability to detect these previously unknown sites of additional carcinoma, modifi- cations in the algorithm of treatment following successful lumpectomy may be feasible.
7. Treatment Issues
Residual disease and recurrence are related. Residual disease that is untreated may eventually manifest itself as a recurrence, either early (within the first 2 years) or late (following 2 years). One of the issues is that some residual disease is treated by radiation therapy that is currently rou- tinely given and/or adjunctive chemotherapy. Radiation therapy treats a significant portion of residual disease, but
not all. The disease that is not treated presents as recur- rence. It is currently not known which disease can be safely left behind in the breast following surgery as it will be treated adequately by radiation and which disease will not.
Therefore, at this time it is surgically necessary to remove all detected tumor.
As MRI detects more tumor than what we have been able to detect with conventional imaging, there has been much more extensive surgery in the efforts to remove all tumor. Some critics have suggested that the extra surgery may be unnecessary. The question can be turned around and posed whether radiation therapy is necessary in all cases. It may be that there is a role for careful MRI mon- itoring in the patient with complete MRI excision of a tumor and no appreciable undetected disease. These patients may be able to forego radiation therapy. Addi- tionally, careful MRI evaluation may be able to better identify those patients who may benefit from radiation and those who may need more extensive surgery based on size of residual tumor. Faverly and colleagues21have estimated that approximately 50% of invasive ductal carcinomas are of limited extent and may be treated well with limited resection and may not need additional radiation therapy.
Magnetic resonance imaging may be helpful in identifying those patients.
8. Conclusion
For the sometime perplexing problem of positive margins, MRI can be a suitable alternative to blind re-excision. The results can direct appropriate surgery so that the entire carcinoma extent can be excised. Alternatively, the results may indicate which patients would be better served with mastectomy rather than breast conservation. As MRI may identify benign disease, patients should not be recom- mended for mastectomy without histologic proof of addi- tional disease. The real benefit of MRI in patients with close or positive margins is not to evaluate the immediate postoperative margin for microscopic residual disease, as the surgeon is planning on re-excision regardless of the MRI result. Rather, the benefit lies in the detection of bulky additional disease or disease entirely separate from the lumpectomy site. As MRI is used more and more pre- operatively to stage patients, the issue of residual disease following initial attempt at lumpectomy may be less of a problem in the future than is currently found in clinical practice.
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