The presentation of occult breast carcinoma (OBC) is not highlighted by an abnormal mammogram or identifiable breast mass but instead only malignant axillary metastases (mostly adenocarcinoma). It was first described by Halsted in 1907, and the prevalence in all breast cancer ranges from 0.3% to 1%. Despite advanced diagnostic tools with high sensitivities (ultrasonography, mammography, and magnetic resonance imaging (MRI)), the diagnosis and appropriate management remains controversial.
Surgical treatment of OBC comprises mastectomy and axillary dissection, though the primary tumor is not found in most cases.1,2 Several recent studies have advocated the necessity/rationality of mastectomy or breast preservation with the dissection of axillary lymph nodes. Vlastos et al3 presented data from 45 women with axillary metastases and reported no significant difference between mastectomy and breast preservation in locoregional recurrent distant metastases, or for 5-year survival (75% vs. 79%). However, a study of 51 women by Wang et al reported that patients having mastectomy had better disease-free survival and overall survival (OS) compared with those having no local treatment of the breast.4
The present study describes our experience with women who had OBC and who presented with axillary metastases. The results of the present study may provide more clinical evidence for the surgical management of OBC.
Ethical approval of the study protocol
The study protocol was approved by the Ethics Board of Peking Union Medical College (Beijing, China).
Patients and follow-up
Seventy-seven patients who presented to the Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CIH, CAMS) from 1968 to 2011 with a diagnosis of axillary metastases from an unknown primary tumor were reviewed. The patient population was identified through a search of the database maintained by the Department of Medical Informatics of CIH, CAMS. Of the 77 patients, two patients were lost to follow-up and eight subjects refused surgical treatment. Thus, 67 patients (90.4%) were included in this analysis.
All patients underwent excisional biopsy. The diagnosis of axillary metastasis was confirmed through cytological or pathological examination by the Department of Pathology of CIH, CAMS. Moreover, all subjects had a negative physical examination, bilateral mammogram, breast ultrasound, and screen for distant metastases. Patients who were diagnosed as having a T0 N1-2 M0 carcinoma using the Union for International Cancer Control-American Joint Committee on Cancer (UICC-AJCC) classification were presumed to have OBC, and the workup and treatment plans were based on this assumption.
Grouping based on treatments
The 67 cases (median age, 51 (range, 36-74) years) were classified into three groups. Forty-two patients were treated with mastectomy+axillary lymph node dissection (ALND), 16 with ALND+radiotherapy (RT) and nine with ALND only. Sixty patients (89.6%) received chemotherapy. Thirty-four patients (50.7%) with either estrogen receptor (ER)- or progesterone receptor (PR)-positive OBC or ER- and PR-positive OBC received hormonal therapy.
Statistical analyses were carried out using SPSS v12.0 (SPSS, Chicago, IL, USA). OS and recurrence-free survival (RFS) were analyzed by the Kaplan-Meier method and compared using the log-rank test. P <0.10 (two-tailed) was regarded as significant. A Cox proportional hazards regression method was used for multivariate analyses.
The clinical characteristics and postoperative therapies are shown in Table 1. Thirty-six cases (85.7%) underwent post-operative chemotherapy in the mastectomy+ALND group, 15 cases (93.7%) in ALND+RT group, but none of the ALND-only group received chemotherapy.
Because of the long time-span of this review, only 16 patients received MRI. Six cases (37.5%) had positive findings, four of whom (66.6%) were confirmed as having breast cancer by immunohistochemical means. Twelve patients underwent positron emission tomography-computed tomography (PET-CT) and suspicious lesions were found in four of these subjects. However, only one of them (50%) were confirmed as having breast cancer after surgery. Five of the MRI-negative and five of the PET-CT-negative patients did not receive a mastectomy, so estimating the specificities of these two diagnostic methods is difficult.
Among the patients treated with mastectomy+ALND, primary breast carcinomas were identified in 19 cases, in which 15 lesions were local and four were diffused. The pathological characteristics are shown in Table 2.
The median follow-up was 62.2 months (range, 0.6-328.0 months). The curves of survival analyses are presented in Figure 1. Kaplan-Meier analyses showed no significant difference in the prevalence of OS and RFS between the three groups (OS, P=0.494; RFS, P=0.397). For the mastectomy+ALND group, there was no significant difference in OS (P=0.078) and RFS (P=0.328) between patients treated with RT and those whithout.
The 1-, 5-, and 10-year OS and RFS between the three groups are shown in Table 3. The prevalence of local recurrence was 11.9% for mastectomy+ALND, 18.8% for ALND+RT and 11.1% for ALND-only, respectively; the prevalence for distant recurrence was 2.4%, 12.5%, and 11.1%, respectively. However, the Wilcoxon analysis showed no significant difference in OS or RFS between the different treatment groups (OS: P=0.569; RFS: P=0.672).
The results of univariate and multivariate survival analyses are shown in Table 4. Expression of the PR had an important impact on OS and RFS (Figure 2). Compared with PR-negative subjects, PR-positive individuals obtained better survival outcomes and a lower prevalence of recurrence (OS: P=0.057; RFS: P=0.062). Cox proportional hazards regression analyses also suggested that expression of the PR was associated with OS.
The diagnosis of OBC
If excisional or needle biopsy of axillary masses suggests metastatic adenocarcinomas without obvious lesions in the breast, a diagnosis of OBC is very likely. However, detailed histological studies such as hormone receptor and human epidermal growth factor receptor 2 (HER2)/neu status can be helpful for supporting the diagnosis of a breast primary tumor.5 Positive staining for the ER and PR are suggestive of breast cancer in about 50% of the subjects.
However, before a diagnosis of OBC is made, imaging such as mammography, ultrasonography, MRI, PET, and thermography should be made to exclude the positive finding of a primary site in the breast. In particular, MRI and PET have been shown to be highly sensitive for the detection of OBC in patients in whom conventional imaging has failed. The prevalence of identification of primary breast tumors by MRI ranges from 35% to 86% in different reports, with high sensitivity but low specificity.6-9 In the present study, 16 patients received MRI and only six cases (37.5%) had positive findings, four of whom (66.6%) were confirmed as having breast cancer by immunohistochemical analyses. Twelve patients underwent PET-CT and suspicious lesions were found in four of these subjects. However, only two of them (50%) were confirmed as having breast cancer after surgery.
Management of OBC
The management of OBC is controversial because large clinical trials are lacking and because the prevalence of OBC is <1% of all cases of breast cancer. Two main options for the management of OBC are available: ALND with or without mastectomy. For maximum locoregional control, complete staging and prognostic information, ALND is recommended as standard treatment for all patients with OBC. We found that those who did not receive ALND had a significantly poorer prognosis with regard to OS compared with patients treated with ALND (mastectomy+ALND, ALND+RT, and ALND-only; P=0.011, data not shown).
To our surprise, there was no significant difference in OS and RFS between the mastectomy+ALND, ALND+RT, and ALND-only groups. This finding was not in accordance with several former studies.1,10 This result might be because the results were affected by the small sample size and relatively short follow-up for the ALND-only group. Nevertheless, these findings also suggested that there was no significant difference in outcomes between mastectomy and breast-preserving surgery. In the future, the role of postoperative RT should be evaluated in controlled studies with a larger sample size.
Several clinicopathological features have been regarded as prognostic factors for OBC, including ER expression, number of lymph nodes, and triple-negative tumors.1,11,12 Nevertheless, none of these features were shown to be significant in the present study. However, we found that expression of the PR was an essential prognostic factor for OBC. The predictive function of the PR in ER-negative breast cancers had been confirmed,13 but the independent influence of the PR on OS and recurrence of breast cancer has not. Our results are consistent with the conclusions of several other studies.14 The specific mechanism of the PR on breast-cancer outcomes has been investigated,15 but further studies are needed.
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Keywords:© 2013 Chinese Medical Association
occult breast carcinoma; surgical treatment; prognostic analysis