Occult Primary Breast Cancer

Three important conclusions are agreed upon regarding this clinical entity:
- Prognosis of occult primary breast cancer is the same or slightly better than women with classic stage IIA disease (T0, N1, M0)
- An exhaustive workup for the non-breast primary is usually not fruitful
- Treatment of the breast in some manner decreases the risk of local failure over time
Occult primary breast cancer was first recognized by William Halsted:
- Who described three patients presenting with axillary tumors that were eventually found to represent breast cancer
In modern series:
- Occult breast cancer accounts for 0.1% to 0.8% of all newly diagnosed breast cancers:
- The incidence has not decreased with improvements in breast imaging
Differential diagnosis:
- In general:
  - Palpable axillary nodes are more often related to benign rather than malignant disorders:
    - 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% or higher:
      - The vast majority are women:
        Although occult primary breast cancer has been reported in men:
        It is very rare
- Other neoplasms that may present with axillary nodal involvement are:
  - Lymphomas
  - Melanomas
  - Sarcomas
  - Thyroid cancers
  - Skin cancers
  - Lung cancers
  - Less often:
    - Uterine, ovarian, sweat gland, or gastric cancers
- In approximately 30% of cases:
  - The primary site is never identified
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 and sometimes electron microscopy can help to narrow the differential diagnosis
- 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 immunohistochemical staining for the following markers:
    - Carcinoembryonic antigen (CEA)
    - Cytokeratins 7 and 20
    - Estrogen receptor (ER) and progesterone receptor (PR)
    - Gross cystic disease fluid protein-15:
      - GCDFP-15:
        Is identified by staining with the monoclonal antibody BRST2
    - Mammaglobin
    - Thyroid transcription factor (TTF-1)
    - CA125
  - 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, CA125, and BRST2
    - 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:
        Not in the lower gastrointestinal tract
    - The pattern of CK20 and CK7 may be particularly helpful in suggesting a primary site:
      - The presence of CK7 and absence of CK20:
        Favors a diagnosis of breast cancer
    - TTF-1:
      - Is rarely positive in breast cancers:
        While it is positive in 70% to 80% of non-squamous cancers arising in the lung
    - CA-125:
      - Is commonly positive in ovarian carcinomas:
        But is positive in about 10% of breast cancers
    - 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:
      - BRST2 is positive in 65% to 80% of cases:
        Is relatively specific for breast cancer:
        Rarely, it is positive in:
        Skin adnexal tumors, endometrial cancers, and salivary gland tumors
    - While mammaglobin is more sensitive, it is less specific for breast cancer:
      - Gynecologic, lung, urothelial, thyroid, colon and hepatobiliary tumors may stain positive:
        Both stains are thus typically used together
  - 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% 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)
Modified radical mastectomy has been the traditional surgical treatment for many years
Previously, the primary breast cancer was found in the mastectomy specimen:
- 40% to 80% of the time, but with the advent of much better mammography and ultrasound along with breast MRI, this rate is much lower now
However, what was true then and still holds today:
- Is that no treatment to the breast itself results in an unacceptably high local recurrence rate
An alternative to a modified radical mastectomy:
- Is complete ALND followed by whole-breast irradiation
Axillary dissection:
- Provides local control while also fine tuning staging
Theoretically the whole-breast radiation:
- Should control any subclinical disease in the breast not detected on imaging
Primary radiation to the breast, axilla, and supraclavicular area without any surgery of the breast or axilla:
- Results in higher local and regional recurrence compared to surgery and radiation combined
Axillary node dissection and whole-breast irradiation:
- Has been found to have equivalent survival as a modified radical mastectomy
A recent meta-analysis of seven studies and more than 240 patients with occult primary breast cancers (0.3% to 0.8% of all breast cancers):
- Found 39% were treated with ALND and radiation while 47% had modified radical mastectomy and 15% had ALND alone
- With a mean follow-up of 5 years:
  - The study found no difference in local regional recurrence (12.7% vs 9.8%), distant metastasis (7.2% vs 12.7%), or mortality (9.5% vs 17.9%) between ALND and radiation vs modified radical mastectomy (all p>0.16)
ALND with radiation was superior to ALND alone in terms of local regional recurrence (12.7% vs 34.3%, p < 0.01) and trended towards improved survival but this was not statistically significant (P=0.09)
References:
- Barton SR, Smith IE, Kirby AM, Ashley S, Walsh G, Parton M. The role of ipsilateral breast radiotherapy in management of occult primary breast cancer presenting as axillary lymphadenopathy. Eur J Cancer. 2011;47:2099-2106. PMID: 21658935. http://www.ncbi.nlm.nih.gov/pubmed/21658935
- Dockery MB, Gray HK, Pierce EH. Surgical significance of isolated axillary adenopathy. Ann Surg. 1957;145:104-107. http://www.ncbi.nlm.nih.gov/pubmed/13395289
- Macedo FI, Eid JJ, Flynn J, Jacobs MJ, Mittal VK. Optimal surgical management for occult breast carcinoma: a meta-analysis. Ann Surg Oncol. 2016;23:1838-1844. https://www.ncbi.nlm.nih.gov/pubmed/26832884
- Rueth NM, Black DM, Limmer AR, et al. Breast conservation in the setting of contemporary multimodality treatment provides excellent outcomes for patients with occult primary breast cancer. Ann Surg Oncol. 2015;22:90-95. [epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/25249256
- Walker GV, Smith GL, Perkins GH, et al. Population-based analysis of occult primary breast cancer with axillary lymph node metastasis. Cancer. 2010;116:4000-4006. PMID: 20564117. http://www.ncbi.nlm.nih.gov/pubmed/20564117
- Woo SM, Son BH, Lee JW, et al. Survival outcomes of different treatment methods for the ipsilateral breast of occult breast cancer patients with axillary lymph node metastasis: a single center experience. J Breast Cancer. 2013;16:410-416. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893343/