Axillary node metastases with occult primary breast cancer

INTRODUCTION — Cancer of unknown primary site (CUP), defined as the presence of metastatic cancer with an undetectable primary site at the time of presentation, is not a common clinical entity. Although the exact incidence is difficult to ascertain, CUP accounted for 2 percent of all cancer diagnoses in the Surveillance, Epidemiology and End Results (SEER) registries between 1973 and 1987 [1].

Within the category of CUP, tumors from many primary sites with varying biologic behavior are represented. Approximately 70 percent are adenocarcinomas, 15 to 20 percent are poorly differentiated carcinomas, and an additional 10 percent represent poorly differentiated adenocarcinomas. The remainder are squamous cell, neuroendocrine, or poorly differentiated neoplasms. (See "Overview of the classification and management of cancers of unknown primary site".)

The prognosis for most patients with CUP is poor. However, substantial improvements have been made in treating some subsets. The identification of specific subgroups of treatable patients has been made possible by the development of specialized immunohistologic techniques that can aid in tumor characterization (table 1) and by the recognition of several clinical syndromes that are predictive for a durable response to systemic therapy.

One such subgroup consists of women (rarely men) who have adenocarcinoma or poorly differentiated carcinoma in the axillary lymph nodes and who have no evident primary breast lesion or distant disease spread after completion of the routine staging evaluation. Such patients are potentially curable when managed according to standard guidelines for anatomic stage II breast cancer.

This topic review will focus on the treatment of women with adenocarcinoma or poorly differentiated carcinoma in axillary nodes who do not have an evident primary breast cancer. The identification and management of other subgroups of patients with CUP is discussed in detail elsewhere, as is the general approach to neoplasms of unknown primary site. (See "Adenocarcinoma of unknown primary site" and "Overview of the classification and management of cancers of unknown primary site".)

In this topic, we will use the terms "woman/en" or "patient" to describe genetic females. However, we recognize that not all people with breasts identify as female, and we encourage the reader to consider transgender and gender nonbinary individuals as part of this larger group.

INCIDENCE AND DIFFERENTIAL DIAGNOSIS — Occult primary breast cancer was first recognized by William Halsted, who described three patients presenting with axillary masses that were eventually found to represent breast cancer [2]. In modern series, occult breast cancer accounts for 0.1 to 0.8 percent of all newly diagnosed breast cancers [3-10], and the incidence has not decreased with improvements in breast imaging [5,8].

Differential diagnosis — In general, palpable axillary nodes are more often related to benign rather than malignant disorders [11]. However, when cancer is identified, the most common tumor causing axillary lymphadenopathy is breast cancer. In several series, the incidence of breast cancer in mixed populations of men and women with metastatic axillary adenopathy is 50 percent or higher [12-15]. The vast majority are women; although occult primary breast cancer has been reported in men, it is rare [16].

Other neoplasms that may present with axillary nodal involvement are lymphomas, melanomas, sarcomas, thyroid cancers, skin cancers, lung cancers, and less often, uterine, ovarian, sweat gland, or gastric cancers [13]. In approximately 30 percent of cases, the primary site is never identified [6,13].

INITIAL DIAGNOSTIC WORKUP

Biopsy — The first step in the diagnostic workup of a patient with unexplained axillary adenopathy is a biopsy. Besides standard light microscopic examination of hematoxylin and eosin-stained sections, other techniques such as immunohistochemistry (IHC) and sometimes electron microscopy can help to narrow the differential diagnosis. The remainder of this topic review will focus on patients who are found to have an adenocarcinoma or poorly differentiated carcinoma in the axillary nodes. (See "Poorly differentiated cancer from an unknown primary site", section on 'Electron microscopy'.)

Immunohistochemistry — The pathologic examination of a biopsy specimen for an isolated axillary lymph node metastatic adenocarcinoma or poorly differentiated carcinoma in a woman should include IHC staining for the following markers:

●Carcinoembryonic antigen (CEA)

●Cytokeratins 7 and 20

●Estrogen receptor (ER) and progesterone receptor (PR) [17]

●Gross cystic disease fluid protein-15 (GCDFP, identified by staining with the monoclonal antibody BRST2)

●Mammaglobin

●Thyroid transcription factor (TTF-1)

●Cancer antigen (CA) 125

Men should have routine staining for prostate cancer markers as well.

While none of these markers is sufficiently sensitive or specific to be used alone, certain patterns of expression favor the diagnosis of an occult breast cancer (positive staining for CEA, CK7, ER/PR, mammaglobin, CA 125, and BRST2, and negative staining for CK20 and TTF-1).

CEA is a sensitive marker for adenocarcinomas of the breast, lung, and gastrointestinal tract, but does not help to distinguish among these sites of origin. On the other hand, differential expression of cytokeratins (CKs) can assist in this differentiation. CK20 is a low molecular weight cytokeratin that is normally expressed in the gastrointestinal epithelium, urothelium, and in Merkel cells; CK7 is expressed by tumors of the lung, ovary, endometrium, and breast, and not in the lower gastrointestinal tract. The pattern of CK20 and CK7 may be particularly helpful in suggesting a primary site (table 2). The presence of CK7 and absence of CK20 favors a diagnosis of breast cancer [18].

TTF-1 is rarely positive in breast cancers, while it is positive in 70 to 80 percent of nonsquamous cancers arising in the lung. CA 125 is commonly positive in ovarian carcinomas, but is positive in about 10 percent of breast cancers. As with ER/PR, its presence in an axillary node, particularly in conjunction with other compatible IHC findings, lends support to a diagnosis of an occult breast primary.

Although positive staining for ER and/or PR supports a possible diagnosis of breast cancer, these markers are nonspecific and they may also be expressed in ovarian, uterine, lung, stomach, thyroid, and hepatobiliary cancers. However, ER/PR staining of an axillary node is compelling evidence of a primary breast cancer.

Other breast cancer-specific IHC stains are BRST2 (for GCDFP) and mammaglobin [18-21]. BRST2 is positive in 65 to 80 percent of cases and is relatively specific for breast cancer; rarely, it is positive in skin adnexal tumors, endometrial cancers, and salivary gland tumors [18,19,22,23]. While mammaglobin is more sensitive, it is less specific for breast cancer (gynecologic, lung, urothelial, thyroid, colon and hepatobiliary tumors may stain positive [18]), and both stains are thus typically used together.

Human epidermal growth factor receptor 2 (HER2) immunostaining is not generally useful for the differential diagnosis of a carcinoma arising in the axillary nodes as it lacks specificity. Furthermore, only 18 to 20 percent of breast cancers overexpress this protein. However, assay for HER2 overexpression by IHC or fluorescent in situ hybridization (FISH) is a routine component of the evaluation of all breast cancers as it permits the identification of those women who are most likely to respond to treatments targeting HER2 (eg, the therapeutic monoclonal antibody trastuzumab). (See "HER2 and predicting response to therapy in breast cancer".)

Breast examination and mammography — In addition to histologic analysis of the biopsy specimen, the diagnostic workup of a patient diagnosed with an adenocarcinoma or a poorly differentiated carcinoma in the axillary lymph nodes is initially targeted toward finding a breast primary carcinoma. A complete physical examination of both breasts is indicated as well as diagnostic mammography [24].

A nonpalpable, clinically occult lesion is identified mammographically in 10 to 20 percent of cases [4,25,26]. However, although mammography may provide useful information, it may also be misleading. Many occult nonpalpable tumors are missed because of their relatively small size (in one series 30 percent of occult breast primaries were 5 mm or less in diameter [26]) and because they are obscured on the mammogram by dense fibroglandular tissue [27]. Furthermore, an abnormal mammogram does not necessarily indicate breast cancer [17,28]. Suspicious findings warrant biopsy to confirm the clinical suspicion, and a negative mammogram in the appropriate clinical setting should prompt further imaging evaluation of the breast with ultrasound and/or breast magnetic resonance imaging (MRI). (See "Breast imaging for cancer screening: Mammography and ultrasonography".)

Breast MRI — Bilateral breast magnetic resonance imaging (MRI) is now considered the standard approach to evaluation of the breasts in patients with axillary node metastases and occult primary breast cancer, if mammography has been negative [24]. (See "Adenocarcinoma of unknown primary site", section on 'Females with axillary lymph node metastases'.)

Breast MRI is more sensitive than either mammography or breast ultrasound for detection of invasive breast cancers. Data from several small series suggest that breast MRI can detect a primary breast cancer in approximately 75 percent of women who present with axillary adenocarcinoma/poorly differentiated carcinoma and a negative clinical examination and mammogram (table 3) [29-38]. Furthermore, the identification of a primary breast cancer by MRI may facilitate breast-conserving surgery instead of mastectomy.

A systematic literature review on the clinical utility of breast MRI in occult breast cancer included eight retrospective studies, totaling 250 patients [39]. A lesion suspect for primary breast cancer was located by MRI in 72 percent of cases (pooled mean), which in 85 to 100 percent of cases represented a malignant breast tumor. The pooled sensitivity and specificity of MRI for breast cancer detection in the only two studies that reported histopathologic confirmation was 90 and 31 percent, respectively. Breast MRI revealed a lesion that was amenable to lumpectomy in about one-third of cases, although some of the patients who were eligible for lumpectomy elected to undergo mastectomy instead.

The main problem with breast MRI is its high false-positive rates (up to 29 percent of all MRI scans in one study [40]) and difficulty in localizing small contrast-enhancing foci. All suspicious findings on MRI require pathologic confirmation. Some lesions found on MRI can be identified on subsequent, targeted "second-look" ultrasound (US) and may then be biopsied under US guidance. US correlate findings have a high likelihood of malignancy. For the remaining lesions, targeting requires MRI guidance. Breast MRI should be performed with a dedicated breast coil by expert breast imaging radiologists at institutions that have the capability to perform MRI guided needle biopsy and/or wire localization of the findings [29,31,40-43]. (See "Diagnostic evaluation of suspected breast cancer", section on 'Breast MRI' and "MRI of the breast and emerging technologies", section on 'Detection of occult primary breast cancer in women with axillary metastases'.)

MANAGEMENT OF PATIENTS WITH NORMAL IMAGING WORKUP — In the absence of a palpable breast mass and normal imaging workup of both breasts, the mammary origin of a metastatic adenocarcinoma/poorly differentiated carcinoma to the axillary lymph nodes cannot be established with certainty. However, if the histologic and immunohistochemical analysis is compatible, these patients are treated according to established guidelines for anatomic stage II breast cancer (table 4).

Completion of the staging workup — Extensive workup evaluation is not necessary. Recommendations from the National Comprehensive Cancer Network for workup of patients with isolated axillary metastases from adenocarcinoma or a poorly differentiated carcinoma suggest only a chest and abdominal computed tomography scan [24]. As with patients who have an identified breast primary and axillary nodal metastases, radionuclide bone scan is reserved for symptomatic women or those with an elevated serum alkaline phosphatase. The utility of PET scanning is controversial. (See "Clinical features, diagnosis, and staging of newly diagnosed breast cancer".)

Locoregional treatment — All patients should undergo axillary lymph node dissection (ALND). Besides providing prognostic information that will guide further treatment, dissection aids local control. About one-half of patients with occult breast primaries will be found to have four or more positive lymph nodes, an indication for postmastectomy chest wall irradiation [44,45]. (See 'Postmastectomy chest wall RT' below and "Overview of management of the regional lymph nodes in breast cancer".)

The optimal treatment of the ipsilateral breast is controversial. For women who do not have a discrete lesion identified by breast imaging, the options are mastectomy, breast-conserving treatment using whole breast radiation therapy (RT), and observation alone. Patients who undergo mastectomy with ALND may have a more favorable outcome compared with patients undergoing ALND. However, the same study showed that mastectomy and ALND had similar outcomes with whole breast RT and ALND [46].

Mastectomy — Although breast-conserving therapy for occult breast cancer with axillary node involvement has been described [47], the standard approach is to perform a modified radical mastectomy (MRM) at the time of ALND. A breast malignancy will be found upon histologic review of the mastectomy specimen in approximately 65 percent of patients (table 5) [3-5,7,8,15,45,46,48-51]. The primary tumor is usually less than 2 cm in diameter; in occasional patients, only carcinoma in situ is identified. The benefits of local treatment were addressed in a retrospective analysis of 51 cases of occult breast cancer in which women who had mastectomy had a markedly lower rate of local recurrence compared to those who had no local therapy (77 versus 26 percent) [52]. Furthermore, disease-free and overall survival were also superior in the mastectomy group.

Radiation — The role of whole breast RT as a breast-conserving alternative to mastectomy is unclear. There are no randomized trials comparing this approach to mastectomy, and the only available data are from small retrospective case series. In published reports limited to patients with occult breast cancer, local control rates with primary whole-breast RT range from 73 to 100 percent (table 6) [5,9,46,49,51,53-55]. In one of the largest series from the Institut Curie, 32 of 45 patients presenting with an occult breast cancer and axillary metastases underwent whole breast RT, while the remainder had mastectomy [38]. No significant difference was detected between mastectomy and breast preservation in locoregional recurrence (15 versus 13 percent), distant metastasis (31 versus 22 percent) or five-year survival (75 versus 79 percent, respectively). Similar comparative survival rates following mastectomy and whole-breast RT have been reported in smaller series from M D Anderson and Memorial Sloan Kettering [9,49].

In a later report of 53 patients with occult breast cancer, there was a trend toward lower five-year risk of an ipsilateral breast tumor recurrence in patients who received RT compared with those who did not (16 versus 36 percent) [56]. Similarly, the five-year rate of locoregional recurrence was lower in the RT group (28 versus 54 percent) and breast cancer-specific survival was significantly higher (72 versus 58 percent, p=0.0073).

Observation only — Observation of the breast without definitive local therapy is generally not recommended at most institutions, given the risks of tumor recurrence and possibly decreased survival.

In some of the more recent case series of patients with an adenocarcinoma of unknown primary in the axillary nodes, an occult primary breast cancer has been identified in fewer mastectomy specimens, perhaps as a result of improvements in imaging modalities (eg, breast magnetic resonance imaging) [7,49,51]. These data, in conjunction with case reports suggesting that survival is similar regardless of whether the breast is treated or not [44,49], have led some to question the necessity of treating the ipsilateral breast [45,49,57].

A compilation of published data on the local recurrence rate in the ipsilateral breast with cases of occult primary breast cancer when the ipsilateral breast is not treated is provided in the table (table 7) [7,44,49,54,57-61]. Overall, approximately one-half of these women will develop an in-breast local recurrence.

Although some reports suggest that observation of the breast does not adversely influence survival, at least three series suggest otherwise [5,10,15]:

●One report consisted of 34 women who presented with axillary metastases and an occult primary breast cancer, all of whom had excisional biopsy of the axillary mass [15]. Eighteen (51 percent) also had a mastectomy, of whom 13 received adjuvant chemotherapy or RT. Of the 16 women who did not have initial mastectomy, eight had no further treatment while eight underwent either chemotherapy, RT, or both. Following treatment, patients were followed for an average of 72 months.

There was a significant difference in outcomes between the surgery and non-surgery groups. Of the 16 women who did not undergo surgery, 13 (81 percent) recurred, as compared to 6 of the 17 (36 percent) who had mastectomy. Of the women for whom follow-up data were available at five years, a significantly greater number of those who had a mastectomy remained alive (8 of 11 versus 5 of 14 [73 versus 36 percent]). Further analysis of the subgroup of patients who received standard adjuvant therapy revealed that seven of eight patients who did not undergo mastectomy died of their disease, compared to only 3 of 13 patients who did.

●An analysis of the Surveillance, Epidemiology and End Results (SEER) database from 1983-2006 identified 750 cases of occult breast cancer [10]. Of the 470 patients who underwent mastectomy or breast-conserving therapy, the 10-year overall survival was significantly higher than it was for the 126 patients who underwent ALND only (65 versus 59 percent; p=0.02) or the 94 patients undergoing observation only with no surgery (48 percent, p=0.04 for the comparison). Mastectomy did not improve outcomes compared with breast-conserving therapy.

Adjuvant systemic therapy — The benefit of adjuvant systemic therapy has not been systematically studied among women presenting with axillary metastases and an occult primary breast cancer. At least one of the retrospective reports notes a significantly greater survival among the 14 patients who received adjuvant chemotherapy as compared to 28 who did not (93 versus 64 percent five-year survival, respectively) [49].

It seems reasonable to extrapolate from modern treatment principles for clinically apparent breast cancer. The addition of trastuzumab to adjuvant chemotherapy improves outcomes in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing tumors. The addition of pertuzumab to trastuzumab and multiagent chemotherapy in the neoadjuvant setting has been shown to improve pathologic complete response in patients with axillary node-positive breast cancer and can also be used in occult breast cancer. Adjuvant hormone therapy is recommended after the completion of chemotherapy for women with hormone-responsive tumors.

The rationale for adjuvant systemic therapy, specific data supporting the use of adjuvant hormone therapy, chemotherapy, and trastuzumab, and a more thorough discussion of recommendations for such therapy in premenopausal and postmenopausal women with either hormone responsive or hormone nonresponsive breast cancer are discussed elsewhere. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer".)

Postmastectomy chest wall RT — The addition of postmastectomy irradiation (RT) in high-risk women reduces the risk of locoregional recurrence, increases disease-free survival, and reduces a woman's risk of dying from breast cancer. The topic of postmastectomy chest wall RT is discussed elsewhere.

Prognosis — Reported five-year survival rates after treatment of an occult primary breast cancer with axillary metastases range from 59 to 93 percent, averaging about 75 percent (table 8) [3,5,15,25,38,45,48,49,54,62,63]. Some authors have suggested that the prognosis for such women is better than that reported for anatomic stage II clinically apparent breast cancer [3,4,44,45,48,57,64]. However, this is a controversial issue because of the marked heterogeneity in adjuvant treatment (a factor that clearly affects survival) in many of the older large surveys from which the prognostic estimates for node-positive clinically apparent breast cancer were derived, and the limited duration of follow-up in reports of patients treated for occult breast cancer.

In the 2017 cancer statistics report from the American Cancer Society, the five-year survival among patients diagnosed with breast cancer was 90 percent [65]. This result compares favorably to that reported in the series of occult breast cancers specifically. However, survival for women with node-negative breast cancer declines over time, and it may be as low as 30 percent at 20 years [66]. Because of the small size and limited follow-up duration of the available reports of women with axillary metastases and an occult primary breast cancer, it is not possible to conclude that outcomes are similar, worse, or better than expected for women treated for clinically apparent primary tumors.

However, in a database study including 572 occult breast cancer cases and over 117,000 patients with clinically apparent breast cancer between 2004 and 2015, patients with occult breast cancer experienced a better survival than patients with clinically apparent breast cancer, when matched according to nodal stage [67].

METASTATIC DISEASE — Women who present with adenocarcinoma or poorly differentiated carcinoma in the axillary nodes, no evident primary breast tumor, and who have metastatic sites in addition to axillary lymph nodes should receive a trial of systemic therapy using guidelines for the treatment of metastatic breast cancer.

Patients with estrogen receptor (ER)- and/or progesterone receptor (PR)-positive tumors may derive major palliative benefit from hormone therapy, with or without targeted therapy (eg, inhibitors of cyclin-dependent kinase 4/6). Chemotherapy is indicated for patients who have ER/PR-negative disease as well as those who fail an initial trial of hormone therapy for hormone-responsive disease. Patients whose tumors overexpress human epidermal growth factor receptor 2 (HER2) by immunohistochemistry (ie, 3+) or by fluorescence in situ hybridization (FISH) should be treated with anti-HER2-directed therapy in combination with other cytotoxic agents. (See "Overview of the approach to metastatic breast cancer" and "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer" and "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer".)

SUMMARY AND RECOMMENDATIONS

●Introduction – Cancer of unknown primary site (CUP), an uncommon clinical entity, is defined by the presence of metastatic disease with an undetectable primary site at the time of presentation. Although the prognosis for most patients with CUP is poor, specific subgroups of treatable patients have been identified using specialized immunohistologic (IHC) techniques that can aid in tumor characterization (table 1) and by the recognition of several clinical syndromes that predict for a durable response to systemic therapy. (See 'Introduction' above.)

●Initial diagnostic workup – Women who present with axillary lymph node metastases who have adenocarcinoma or poorly differentiated carcinoma histology, compatible IHC staining, no other distant metastases and no evidence of a breast cancer primary on clinical examination, mammography, breast ultrasound, and breast magnetic resonance imaging represent a potentially curable subset of individuals with CUP. These women are treated according to guidelines for anatomic stage II breast cancer. (See 'Initial diagnostic workup' above.)

●Completion of the staging workup – Extensive staging evaluation is unnecessary. Guidelines for workup of patients with isolated axillary metastases from adenocarcinoma or a poorly differentiated carcinoma from the National Comprehensive Cancer Network suggest only a chest and abdominal computed tomography scan. Radionuclide bone scans are reserved for symptomatic women or those with unexplained elevations in serum alkaline phosphatase. (See 'Completion of the staging workup' above.)

●Locoregional treatment – We recommend that all patients undergo axillary lymph node dissection (ALND) (Grade 1B). Optimal treatment for the ipsilateral breast is controversial. A standard approach is to perform a modified radical mastectomy (MRM) at the time of ALND. For women who wish to preserve their breast, whole breast radiation therapy is an acceptable option. We suggest not pursuing observation alone for the ipsilateral breast (Grade 2C). (See 'Locoregional treatment' above.)

●Adjuvant systemic therapy – We recommend that all women with axillary nodal metastases and an occult primary breast cancer undergo systemic adjuvant therapy according to published guidelines for anatomic stage II primary breast cancer (Grade 1B). (See 'Adjuvant systemic therapy' above.)

●Metastatic disease – Women with axillary lymph node metastases who have adenocarcinoma or poorly differentiated carcinoma histology, compatible IHC staining, and no evidence of a breast cancer primary but who have evidence of other distant metastases should be treated according to guidelines for metastatic breast cancer. (See 'Metastatic disease' above.)