Breast Conservation Treatment for Patients Presenting with Axillary Lymphadenopathy from Presumed Primary Breast Cancer: The Role of Breast Magnetic Resonance Imaging for Staging

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Breast Conservation Treatment for Patients Presenting with Axillary Lymphadenopathy from Presumed Primary Breast Cancer: The Role of Breast Magnetic Resonance Imaging for Staging Changhu Chen,1 Susan G. Orel,2 Mitchell D. Schnall,2 Eleanor Harris,1 Lawrence J. Solin1 Abstract Three female patients presented with malignant axillary lymphadenopathy presumed to be from primary breast cancer. No evidence of primary cancer was found in the breast on either mammography or breast magnetic resonance imaging (MRI). All 3 patients underwent axillary lymph node dissection and systemic chemotherapy followed by radiation therapy to the breast and regional lymph nodes. Two patients remain relapse free with a follow-up of 3.7 years each. The third patient achieved locoregional control in the ipsilateral breast and regional lymph nodes but relapsed in the contralateral axilla. These 3 cases illustrate the potential for breast conservation treatment for patients presenting with axillary adenopathy from a presumed primary breast cancer but without either mammographic or breast MRI findings. Clinical Breast Cancer, Vol. 3, No. 3, 219-222, 2002 Key words: Computed tomography, Mammography, Radiation therapy, Doxorubicin, Cyclophosphamide

Introduction

Case 1

Breast magnetic resonance imaging (MRI) is more sensitive than mammography in detecting breast cancer. An MRI can identify a primary lesion in the breast in 75%-86% of the patients presenting with axillary lymphadenopathy without mammographic findings.1-3 For the patients who present with malignant axillary adenopathy presumed to be from primary breast cancer but without evidence of primary tumor on mammography, the appropriate treatment is uncertain. We report 3 cases and discuss the results of breast conservation treatment for the patients in this setting.

A 60-year-old woman was found to have a 2.5-cm right axillary lymph node on a routine physical examination. A fineneedle aspiration cytology was performed, and demonstrated metastatic carcinoma. No suspicious lesions were noted on bilateral mammograms and breast ultrasound studies. A metastatic workup, including chest x-ray, bone scan, computed tomography (CT) scan of the chest and abdomen, and liver function tests, were all negative. An MRI of the right breast showed a 1-cm rim-enhancing lesion in the upper outer quadrant of the right breast. An MRI-guided biopsy of the right breast lesion was performed. The pathology showed focal atypical ductal hyperplasia but no carcinoma. A right axillary level I and II lymph node dissection was carried out, and of the 26 lymph nodes evaluated, 1 lymph node was positive for metastatic carcinoma. The tumor was found to be estrogen- and progesterone-receptor negative. The patient was treated with 4 cycles of AC (doxorubicin/cyclophosphamide) chemotherapy, followed by 4 cycles of paclitaxel. Restaging studies included a negative chest x-ray and a negative bone scan. Bilateral mammograms demonstrated only

1Department 2Department

of Radiation Oncology of Radiology Hospital of the University of Pennsylvania, Philadelphia

Submitted: May 10, 2002; Revised: Jun. 24, 2002; Accepted: Jul. 3, 2002 Address for correspondence: Lawrence J. Solin, MD, Department of Radiation Oncology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 2 Donner Building, Philadelphia, PA 19104 Fax: 215-349-5445; e-mail: [email protected]

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MRI Staging and Breast Conservation postsurgical change in the right breast. However, a repeat breast MRI showed a new 1.3-cm mass in the superior aspect of the right breast. These findings were suspicious for primary breast cancer. An MRI-guided needle localization biopsy was performed, and pathology showed benign breast tissue, extensive biopsy-site reaction, fibrocystic change, and focal ductal hyperplasia but no carcinoma. She was subsequently treated with external beam radiation to the right breast using tangent fields to a total dose of 50.4 Gy in 28 fractions using 1.8 Gy per fraction. The patient remains relapse free 3 years after the completion of her radiation therapy and 3.7 years after her initial diagnosis.

Case 2 A 57-year-old woman presented with a 2-cm right axillary mass. Mammography did not show abnormality in her right breast; however, an abnormal area was palpated in the upper outer quadrant of the right breast on physical examination. Right breast lumpectomy of the palpable mass and right axillary lymph node dissection were performed. Pathology revealed proliferative fibrocystic change in the right breast. Of the 18 axillary lymph nodes evaluated, 7 lymph nodes were positive for metastatic, poorly differentiated carcinoma. Estrogen and progesterone receptors were negative. A postoperative MRI of the right breast revealed a 1.4-cm irregular enhancing lesion along the lateral aspect of the biopsy site suspicious for primary tumor. An MRI localization biopsy was planned. However, a repeat breast MRI at the time of the planned biopsy did not reveal the previously seen lesion. A metastatic workup, including a chest x-ray, bone scan, CT scan of the chest and abdomen, and liver function tests, were all negative. The patient received 4 cycles of AC chemotherapy followed by 4 cycles of paclitaxel. The patient was subsequently treated with radiation to the right breast and regional lymph nodes using a 4-field technique (including a posterior axillary boost field) to a total dose of 50.4 Gy to the right breast and 45.0 Gy to the supraclavicular fossa and the axilla using 1.8 Gy per fraction. A repeat breast MRI revealed a suspicious 1.5-cm enhancing lesion in the superior aspect of the right breast. Therefore, an MRI-guided needle localization biopsy was performed, and pathology revealed fat necrosis, mammary atrophy, and focal cytologic atypia consistent with her prior radiation therapy. The patient remains relapse free 2.8 years after radiation treatment and 3.7 years after initial diagnosis.

lymph node dissection showed metastatic carcinoma in all 14 axillary lymph nodes. The patient received 4 cycles of AC chemotherapy, but refused the additionally recommended paclitaxel chemotherapy. She was treated with radiation to the left breast and regional lymph nodes using a 4-field technique (including a posterior axillary boost field) to a total dose of 50.4 Gy to the left breast and 45 Gy to the supraclavicular fossa and the axilla using 1.8 Gy per fraction. She did well until 1 year later when she presented with palpable right (contralateral) axillary lymphadenopathy. A right breast MRI study showed only right axillary lymphadenopathy without a mass lesion in the right breast. Bone scan demonstrated no bony metastases. CT scan of the chest and abdomen and an MRI scan of the brain revealed no evidence of metastatic disease. Right axillary lymph node dissection showed metastatic carcinoma in all 7 axillary lymph nodes. The patient received 4 cycles of docetaxel chemotherapy. She then completed a course of definitive radiation treatment to the right breast and regional lymph nodes using a 4-field technique (including a posterior axillary boost field). The radiation dose was 50.4 Gy to the right breast and 45 Gy to the supraclavicular lymph nodes and the axilla using 1.8 Gy fractions. The patient achieved local control in the ipsilateral breast and regional lymph nodes 2 years after her first course of radiation therapy and 2.8 years after the initial diagnosis of breast cancer.

Discussion Although malignant axillary lymphadenopathy can be secondary to a variety of primary tumors, breast cancer is the most common diagnosis in women presenting with isolated axillary adenopathy.4-6 The presentation of a patient with axillary lymphadenopathy but without a detectable primary breast carcinoma is unusual. The incidence of patients with an axillary lymph node presentation is approximately 0.4% of all patients presenting with carcinoma of the breast.6 The ability of mammography to detect a primary breast cancer in patients presenting with axillary lymph node metastasis is low, with a reported incidence of 0%-56% in detecting an occult primary breast cancer.6 It is important to recognize that patients with an initially negative mammogram may still have a primary carcinoma of the breast. A primary tumor was found in approximately 64% of patients who underwent mastectomy.7 Such findings may indicate that mammography is not sensitive enough to detect all primary breast tumors.

Case 3 A 48-year-old woman self-palpated a left axillary mass. Bilateral breast mammography and ultrasound were performed and showed left axillary lymphadenopathy and a subtle area of tissue distortion in the left subareolar region. Left breast MRI revealed no lesion. Fine-needle aspiration cytology of the left axillary mass confirmed poorly differentiated carcinoma. Metastatic workup, including a bone scan, chest x-ray, CT scan of the abdomen, and serum liver function tests showed no evidence of metastatic disease. Left axillary

220 • Clinical Breast Cancer August 2002

MRI Staging and Breast Conservation The traditional treatment approach for women with an occult breast cancer presenting with isolated axillary adenopathy is a mastectomy. Although the size of the occult breast tumors found in mastectomy specimens are < 1 cm in 64% of patients, 36% of patients are noted to have tumors ≥ 1 cm.6 Tumors ≥ 1 cm in size are not likely to be controlled with definitive radiation to the breast. Breast conservation and definitive radiation have been used to treat patients

Changhu Chen et al Table 1 Patient Profiles Patient 1

Patient 2

Patient 3

60

57

48

49

Side of Axillary Presentation

Right

Right

Left

Right

Histology of Axillary Lymph Nodes

Metastatic carcinoma

Metastatic, poorly differentiated carcinoma

Poorly differentiated carcinoma

Poorly differentiated carcinoma

Negative

Negative

Negative

Negative

1-cm and 1.3-cm lesions

1.5-cm lesion

No lesion

No lesion

Both lesions benign

Benign

None

None

O ther Breast Surgery

None

Lumpectomy for a palpable mass, benign

None

None

Positive Lymph Nodes on Axillary Dissection

1/26

7/18

14/14

7/7

Negative

Negative

Negative

Negative

Chemotherapy

AC x 4 Paclitaxel x 4

AC x 4 Paclitaxel x 4

AC x 4

Docetaxel x 4

Radiation

50.4 Gy to the breast

50.4 Gy to the breast, 45 Gy to the axilla and supraclavicular fossa

50.4 Gy to the breast, 45 Gy to the axilla and supraclavicular fossa

50.4 Gy to the breast, 45 Gy to the axilla and supraclavicular fossa

3.7 years

3.7 years

2.8 years

6 months

Age (Years)

Mammography Breast MRI MRI-Guided Breast Biopsy

Metastatic Workup

Follow-Up After Diagnosis

Abbreviations: AC = doxorubicin/cyclophosphamide; MRI = magnetic resonance imaging

with occult breast cancer.8,9 A series reported by Ellerbroek et al demonstrated a 17% 5-year actuarial risk for a recurrence in the ipsilateral breast.8 A 5-year failure rate of 23% was reported from the Institut Curie.9 Breast conservation treatment in patients with occult primary breast cancer may be feasible with breast MRI for staging. Breast MRI for staging has been shown to be useful in the clinical management of women with early-stage breast cancer.10 Overall, breast MRI offers increased sensitivity over mammography in detecting breast cancer, and Tillman et al reported that the MRI findings affected clinical management in 20% of the patients undergoing evaluation for breast conservation treatment who had undergone MRI staging. The benefit of MRI staging includes identifying multifocal cancer or extensive areas of cancer not seen on mammography, helping to localize a malignant area for biopsy, clarifying suspicious mammographic findings, and sparing patients a breast biopsy.

The Usefulness of MRI in Patients with Negative Mammography Breast MRI is highly sensitive for the detection of breast cancer and may be able to detect mammographically occult cancer in the breast for the patient presenting with malignant axillary adenopathy.1-3 In a series from the University of Pennsylvania, MRI detected a primary breast cancer in 19 of 22 women (86%) with malignant axillary adenopathy and

negative mammographic and physical examination findings.1 The MRI-detected breast cancer was confirmed histopathologically at excisional biopsy or mastectomy in 17 of the 19 patients (89%). Two lesions resolved on follow-up MRI. In a series from Memorial Sloan-Kettering Cancer Center (MSKCC), a primary breast cancer was identified on MRI imaging in 9 of 12 patients (75%).2 Areas of abnormal enhancement were identified in 10 of the 12 women (83%), and no enhancement was identified in the remaining 2 patients (17%). MRI-enhancing lesions were confirmed histopathologically as invasive breast cancer in 8 of 9 patients (89%). No cancer was discovered at surgery in 1 woman with abnormal enhancement. Postmastectomy histopathological examination failed to discover tumors in the breast in 2 women whose breast MRI demonstrated no enhancement. The most common MRI finding was an enhancing mass lesion with irregular or spiculated borders. Breast tumors as small as 4 mm have been detected on MRI imaging.1,2 It is also interesting that MRI-detected breast tumors in patients with a negative mammography are not necessarily small. The median size of the tumor depicted on MRI was 1.7 cm (range, 0.4-3.0 cm) in the University of Pennsylvania series,1 and 1.3 cm (range, 0.7-2.0 cm) in the MSKCC series.2 Ideally, an MRI-guided localization system should be available. However, directed ultrasound examination to the expected location of the MRI-detected lesion may allow for

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MRI Staging and Breast Conservation lesion identification and biopsy if there is no access to MRIguided biopsy. In the MSKCC series, ultrasound examination of the breast in 9 patients with MRI-enhancing lesions found that 3 were negative.2 In the other 6 patients, ultrasound was used to identify and localize solid masses that correlated with the MRI findings. The lesions removed with ultrasound-guided needle localization all proved to correspond to the site of the primary tumor at surgery.

be guided by the MRI findings. For the patients in whom the primary disease is an occult with no evidence of primary breast cancer on either mammogram or breast MRI, optimal management is uncertain. These patients likely have a small tumor burden in the breast which can probably be adequately treated by conventional doses of radiation and adjuvant chemotherapy.

Conclusion The Limitations of Breast MRI Staging One of the limitations of the breast MRI staging is false positivity. Atypical ductal hyperplasia, fibrocystic changes, fibroadenoma, apocrine metaplasia, and fat necrosis can all show as a suspicious enhancing lesion on MRI, leading to further surgical evaluation. In cases 1 and 2 (Table 1), both patients had false-positive MRI findings and underwent MRIguided breast biopsy. In patients with axillary node metastases from presumed primary breast cancer reported from the University of Pennsylvania, false-positive enhancing lesions were reported in 6 of 19 women (32%) who had positive MRI findings.1 In 4 of the 6 women (67%), a true-positive lesion elsewhere in the breast was also identified.1 Nevertheless, a surgical or core-needle biopsy should be performed to clarify the diagnosis for any patient with a suspicious MRI finding. Although breast MRI is very sensitive in detecting breast cancer, false-negative findings were reported in the University of Pennsylvania series in 2 of 22 patients (9%).1 MRI may not be sensitive enough to detect tumors < 2 mm. On the other hand, some lesions as large as 17 mm were not visible on MRI. The clinical importance of a negative MRI in the setting of isolated axillary metastases is not clear at this time. A negative breast MRI most probably represents a small tumor burden in the breast of the patient presenting with axillary adenopathy if such a patient has a primary breast cancer. Thus, conventional doses of radiation therapy to the breast and regional lymph nodes are probably necessary for locoregional control in this setting.

Recommendations for Isolated Axillary Adenopathy Women presenting with isolated axillary adenopathy should have a complete physical examination, bilateral mammography, and a metastatic workup. If no breast abnormality is identified on either mammography or physical examination, the patient should undergo a breast MRI study because of the high rate of detecting a primary tumor in the breast. If a breast lesion is depicted on an MRI and pathologically confirmed as breast cancer, then breast conserving surgery may

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In summary, we report 3 patients, all of whom presented with axillary lymphadenopathy but no definite primary breast cancer on mammography, physical examination, or MRI. All 3 patients were treated with doxorubicin-based systemic chemotherapy and definitive radiation therapy. Two patients remain relapse free after a follow-up of 3.7 years each. The third patient achieved local control in the ipsilateral breast and regional lymph nodes after chemotherapy and radiation, but relapsed in the contralateral axilla 1 year after her first course of radiation therapy. Although the number of patients is small and the follow-up is short, breast conservation therapy may be one appropriate option for treatment in this setting.

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