Axillary node metastases with occult primary breast cancer
- Virginia Kaklamani, MD, DSc
Virginia Kaklamani, MD, DSc
- Professor of Medicine
- Leader, Breast Oncology Program
- CTRC, University of Texas Health Science Center San Antonio
- William J Gradishar, MD
William J Gradishar, MD
- Professor of Medicine
- Feinberg School of Medicine
- Northwestern University
- Section Editors
- Daniel F Hayes, MD
Daniel F Hayes, MD
- Section Editor — Breast Cancer
- Professor of Medicine
- University of Michigan School of Medicine
- Anees B Chagpar, MD, MSc, MA, MPH, MBA, FACS, FRCS(C)
Anees B Chagpar, MD, MSc, MA, MPH, MBA, FACS, FRCS(C)
- Section Editor — Breast Surgery
- Associate Professor, Department of Surgery
- Yale University School of Medicine
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 .
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 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".)
- Hainsworth JD, Wright EP, Johnson DH, et al. Poorly differentiated carcinoma of unknown primary site: clinical usefulness of immunoperoxidase staining. J Clin Oncol 1991; 9:1931.
- Halsted WS. I. The Results of Radical Operations for the Cure of Carcinoma of the Breast. Ann Surg 1907; 46:1.
- Baron PL, Moore MP, Kinne DW, et al. Occult breast cancer presenting with axillary metastases. Updated management. Arch Surg 1990; 125:210.
- Fitts WT, Steiner GC, Enterline HT. Prognosis of Occult Carcinoma of the Breast. Am J Surg 1963; 106:460.
- Foroudi F, Tiver KW. Occult breast carcinoma presenting as axillary metastases. Int J Radiat Oncol Biol Phys 2000; 47:143.
- Haupt HM, Rosen PP, Kinne DW. Breast carcinoma presenting with axillary lymph node metastases. An analysis of specific histopathologic features. Am J Surg Pathol 1985; 9:165.
- Kemeny MM, Rivera DE, Terz JJ, Benfield JR. Occult primary adenocarcinoma with axillary metastases. Am J Surg 1986; 152:43.
- OWEN HW, DOCKERTY MB, GRAY HK. Occult carcinoma of the breast. Surg Gynecol Obstet 1954; 98:302.
- Vilcoq JR, Calle R, Ferme F, Veith F. Conservative treatment of axillary adenopathy due to probable subclinical breast cancer. Arch Surg 1982; 117:1136.
- 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.
- Walsh R, Kornguth PJ, Soo MS, et al. Axillary lymph nodes: mammographic, pathologic, and clinical correlation. AJR Am J Roentgenol 1997; 168:33.
- de Andrade JM, Marana HR, Sarmento Filho JM, et al. Differential diagnosis of axillary masses. Tumori 1996; 82:596.
- Copeland EM, McBride CM. Axillary metastases from unknown primary sites. Ann Surg 1973; 178:25.
- Gupta RK, Naran S, Lallu S, Fauck R. Diagnostic value of needle aspiration cytology in the assessment of palpable axillary lymph nodes. A study of 336 cases. Acta Cytol 2003; 47:550.
- Blanchard DK, Farley DR. Retrospective study of women presenting with axillary metastases from occult breast carcinoma. World J Surg 2004; 28:535.
- Namba N, Hiraki A, Tabata M, et al. Axillary metastasis as the first manifestation of occult breast cancer in a man: a case report. Anticancer Res 2002; 22:3611.
- Bhatia SK, Saclarides TJ, Witt TR, et al. Hormone receptor studies in axillary metastases from occult breast cancers. Cancer 1987; 59:1170.
- Dabbs DJ. Immunohistology of metastatic carcinoma of unknown primary. In: Diagnostic Immunohistochemistry, 2nd, Dabbs DJ (Ed), Churchill Livingstone/Elsevier, 2006.
- Han JH, Kang Y, Shin HC, et al. Mammaglobin expression in lymph nodes is an important marker of metastatic breast carcinoma. Arch Pathol Lab Med 2003; 127:1330.
- Leygue E, Snell L, Dotzlaw H, et al. Mammaglobin, a potential marker of breast cancer nodal metastasis. J Pathol 1999; 189:28.
- Watson MA, Dintzis S, Darrow CM, et al. Mammaglobin expression in primary, metastatic, and occult breast cancer. Cancer Res 1999; 59:3028.
- Sasaki E, Tsunoda N, Hatanaka Y, et al. Breast-specific expression of MGB1/mammaglobin: an examination of 480 tumors from various organs and clinicopathological analysis of MGB1-positive breast cancers. Mod Pathol 2007; 20:208.
- O'Connell FP, Wang HH, Odze RD. Utility of immunohistochemistry in distinguishing primary adenocarcinomas from metastatic breast carcinomas in the gastrointestinal tract. Arch Pathol Lab Med 2005; 129:338.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on February 27, 2016).
- Kyokane T, Akashi-Tanaka S, Matsui T, Fukutomi Ta. Clinicopathological Characteristics of Non-palpable Breast Cancer Presenting as Axillary Mass. Breast Cancer 1995; 2:105.
- Leibman AJ, Kossoff MB. Mammography in women with axillary lymphadenopathy and normal breasts on physical examination: value in detecting occult breast carcinoma. AJR Am J Roentgenol 1992; 159:493.
- Kolb TM, Lichy J, Newhouse JH. Occult cancer in women with dense breasts: detection with screening US--diagnostic yield and tumor characteristics. Radiology 1998; 207:191.
- Stevens KJ, Smith SL, Denley H, et al. Is mammography of value in women with disseminated cancer of unknown origin? Clin Oncol (R Coll Radiol) 1999; 11:90.
- Olson JA Jr, Morris EA, Van Zee KJ, et al. Magnetic resonance imaging facilitates breast conservation for occult breast cancer. Ann Surg Oncol 2000; 7:411.
- Chen C, Orel SG, Harris E, et al. Outcome after treatment of patients with mammographically occult, magnetic resonance imaging-detected breast cancer presenting with axillary lymphadenopathy. Clin Breast Cancer 2004; 5:72.
- Obdeijn IM, Brouwers-Kuyper EM, Tilanus-Linthorst MM, et al. MR imaging-guided sonography followed by fine-needle aspiration cytology in occult carcinoma of the breast. AJR Am J Roentgenol 2000; 174:1079.
- Buchanan CL, Morris EA, Dorn PL, et al. Utility of breast magnetic resonance imaging in patients with occult primary breast cancer. Ann Surg Oncol 2005; 12:1045.
- Schorn C, Fischer U, Luftner-Nagel S, et al. MRI of the breast in patients with metastatic disease of unknown primary. Eur Radiol 1999; 9:470.
- Henry-Tillman RS, Harms SE, Westbrook KC, et al. Role of breast magnetic resonance imaging in determining breast as a source of unknown metastatic lymphadenopathy. Am J Surg 1999; 178:496.
- Tilanus-Linthorst MM, Obdeijn AI, Bontenbal M, Oudkerk M. MRI in patients with axillary metastases of occult breast carcinoma. Breast Cancer Res Treat 1997; 44:179.
- Brenner RJ, Rothman BJ. Detection of primary breast cancer in women with known adenocarcinoma metastatic to the axilla: use of MRI after negative clinical and mammographic examination. J Magn Reson Imaging 1997; 7:1153.
- Morris EA, Schwartz LH, Dershaw DD, et al. MR imaging of the breast in patients with occult primary breast carcinoma. Radiology 1997; 205:437.
- Fourquet, A, Meunier, et al. Occult primary cancer with axillary metastases. In: Diseases of the Breast, 3rd edition, Harris, JR, Lippman, ME, Morrow, M, Osborne, CK (Eds), Lippincott, Williams and Wilkins, Philadelphia 2004. p.1047.
- de Bresser J, de Vos B, van der Ent F, Hulsewé K. Breast MRI in clinically and mammographically occult breast cancer presenting with an axillary metastasis: a systematic review. Eur J Surg Oncol 2010; 36:114.
- Bedrosian I, Schlencker J, Spitz FR, et al. Magnetic resonance imaging-guided biopsy of mammographically and clinically occult breast lesions. Ann Surg Oncol 2002; 9:457.
- Floery D, Helbich TH. MRI-Guided percutaneous biopsy of breast lesions: materials, techniques, success rates, and management in patients with suspected radiologic-pathologic mismatch. Magn Reson Imaging Clin N Am 2006; 14:411.
- Liberman L, Bracero N, Morris E, et al. MRI-guided 9-gauge vacuum-assisted breast biopsy: initial clinical experience. AJR Am J Roentgenol 2005; 185:183.
- Kuhl CK, Morakkabati N, Leutner CC, et al. MR imaging--guided large-core (14-gauge) needle biopsy of small lesions visible at breast MR imaging alone. Radiology 2001; 220:31.
- Merson M, Andreola S, Galimberti V, et al. Breast carcinoma presenting as axillary metastases without evidence of a primary tumor. Cancer 1992; 70:504.
- Rosen PP, Kimmel M. Occult breast carcinoma presenting with axillary lymph node metastases: a follow-up study of 48 patients. Hum Pathol 1990; 21:518.
- He M, Tang LC, Yu KD, et al. Treatment outcomes and unfavorable prognostic factors in patients with occult breast cancer. Eur J Surg Oncol 2012; 38:1022.
- Ashikari R, Rosen PP, Urban JA, Senoo T. Breast cancer presenting as an axillary mass. Ann Surg 1976; 183:415.
- Ellerbroek N, Holmes F, Singletary E, et al. Treatment of patients with isolated axillary nodal metastases from an occult primary carcinoma consistent with breast origin. Cancer 1990; 66:1461.
- Patel J, Nemoto T, Rosner D, et al. Axillary lymph node metastasis from an occult breast cancer. Cancer 1981; 47:2923.
- Vlastos G, Jean ME, Mirza AN, et al. Feasibility of breast preservation in the treatment of occult primary carcinoma presenting with axillary metastases. Ann Surg Oncol 2001; 8:425.
- Wang X, Zhao Y, Cao X. Clinical benefits of mastectomy on treatment of occult breast carcinoma presenting axillary metastases. Breast J 2010; 16:32.
- Medina-Franco H, Urist MM. Occult breast carcinoma presenting with axillary lymph node metastases. Rev Invest Clin 2002; 54:204.
- Campana F, Fourquet A, Ashby MA, et al. Presentation of axillary lymphadenopathy without detectable breast primary (T0 N1b breast cancer): experience at Institut Curie. Radiother Oncol 1989; 15:321.
- Varadarajan R, Edge SB, Yu J, et al. Prognosis of occult breast carcinoma presenting as isolated axillary nodal metastasis. Oncology 2006; 71:456.
- Masinghe SP, Faluyi OO, Kerr GR, Kunkler IH. Breast radiotherapy for occult breast cancer with axillary nodal metastases--does it reduce the local recurrence rate and increase overall survival? Clin Oncol (R Coll Radiol) 2011; 23:95.
- van Ooijen B, Bontenbal M, Henzen-Logmans SC, Koper PC. Axillary nodal metastases from an occult primary consistent with breast carcinoma. Br J Surg 1993; 80:1299.
- Feigenberg SJ, Price Mendenhall N, Benda RK, Morris CG. Postmastectomy radiotherapy: patterns of recurrence and long-term disease control using electrons. Int J Radiat Oncol Biol Phys 2003; 56:716.
- FEUERMAN L, ATTIE JN, ROSENBERG B. Carcinoma in axillary lymph nodes as an indicator of breast cancer. Surg Gynecol Obstet 1962; 114:5.
- Haagensen CD. The choice of treatment for operable carcinoma of the breast. Surgery 1974; 76:685.
- Atkins H, Wolff B. The malignant gland in the hospital. Guys Hosp Rep 1960; 1:109.
- Goldhirsch A, Glick JH, Gelber RD, et al. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005; 16:1569.
- Matsuoka K, Ohsumi S, Takashima S, et al. Occult breast carcinoma presenting with axillary lymph node metastases: follow-up of eleven patients. Breast Cancer 2003; 10:330.
- Lloyd MS, Nash AG. 'Occult' breast cancer. Ann R Coll Surg Engl 2001; 83:420.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66:7.
- Weiss RB, Woolf SH, Demakos E, et al. Natural history of more than 20 years of node-positive primary breast carcinoma treated with cyclophosphamide, methotrexate, and fluorouracil-based adjuvant chemotherapy: a study by the Cancer and Leukemia Group B. J Clin Oncol 2003; 21:1825.
- INCIDENCE AND DIFFERENTIAL DIAGNOSIS
- Differential diagnosis
- INITIAL DIAGNOSTIC WORKUP
- - Immunohistochemistry
- Breast examination and mammography
- Breast MRI
- MANAGEMENT OF PATIENTS WITH NORMAL IMAGING WORKUP
- Completion of the staging workup
- Locoregional treatment
- - Mastectomy
- - Radiation
- - Observation only
- Adjuvant systemic therapy
- Postmastectomy chest wall RT
- METASTATIC DISEASE
- SUMMARY AND RECOMMENDATIONS