Inflammatory breast cancer: Pathology and molecular pathogenesis
- Sofia D Merajver, MD, PhD
Sofia D Merajver, MD, PhD
- Professor of Internal Medicine
- University of Michigan Medical School
Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer. De novo IBC refers to primary disease. These patients typically present with pain and a tender, firm, and enlarged breast. The skin over the breast is reddened, warm, and thickened, with a "peau d'orange" (orange skin) appearance (picture 1). In comparison, the inflammatory recurrence of a noninflammatory breast cancer is called secondary disease. It usually develops on the chest wall at the site of previous mastectomy, but can also occur rarely as a distant cutaneous recurrence. The signs and symptoms of IBC arise rapidly compared to non IBC, typically within weeks to six months.
Primary IBC is a relatively rare disorder accounting for approximately 1 to 5 percent of invasive breast cancers [1,2]. However, because of its aggressive nature, it accounts for a greater proportion of cases presenting with more advanced disease. In one report of 752 patients with stage III breast cancer, for example, 24 percent had IBC .
At presentation, almost all women with primary IBC have lymph node involvement and approximately one-third have distant metastases. The long-term prognosis is also relatively poor, which has led to the development of combined modality treatment regimens consisting of neoadjuvant chemotherapy to maximize clinical response, followed by locoregional treatment, and then consolidation chemotherapy [4,5]. (See "Inflammatory breast cancer: Clinical features and treatment".)
The 2010 American Joint Committee on Cancer and the International Union for Cancer Control (AJCC-UICC) TNM breast cancer staging system defines inflammatory breast cancer (IBC) as a clinical-pathologic entity characterized by diffuse erythema and edema (peau d'orange) involving a third or more of the skin of the breast (table 1). These "inflammatory" skin changes are not due to infiltration of inflammatory cells but rather to lymphedema caused by tumor emboli within the dermal lymphatics. However, the diagnosis is based upon the clinical presentation. Although dermal lymphatic involvement supports the diagnosis of inflammatory breast cancer, it is neither necessary nor sufficient in the absence of classical clinical findings.
IBC is designated as primary tumor stage T4d. Tumor presentation with ulceration and/or ipsilateral satellite skin nodules and/or edema are T4b. Not all skin changes qualify as IBC or even locally advanced breast cancer (LABC). Invasion of the dermis alone, such as dimpling of the skin or nipple retraction does not qualify as T4 and may occur in T1, T2, or T3 without changing the classification.
Subscribers log in hereLiterature review current through: Jul 2017. | This topic last updated: Feb 07, 2017.References
- Berg JW, Hutter RV. Breast cancer. Cancer 1995; 75:257.
- Chang S, Parker SL, Pham T, et al. Inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program of the National Cancer Institute, 1975-1992. Cancer 1998; 82:2366.
- Buzdar AU, Singletary SE, Booser DJ, et al. Combined modality treatment of stage III and inflammatory breast cancer. M.D. Anderson Cancer Center experience. Surg Oncol Clin N Am 1995; 4:715.
- Merajver SD, Weber BL, Cody R, et al. Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University of Michigan experience. J Clin Oncol 1997; 15:2873.
- Jaiyesimi IA, Buzdar AU, Hortobagyi G. Inflammatory breast cancer: a review. J Clin Oncol 1992; 10:1014.
- Alpaugh ML, Tomlinson JS, Shao ZM, Barsky SH. A novel human xenograft model of inflammatory breast cancer. Cancer Res 1999; 59:5079.
- Dawood S, Merajver SD, Viens P, et al. International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Ann Oncol 2011; 22:515.
- Kleer CG, van Golen KL, Merajver SD. Molecular biology of breast cancer metastasis. Inflammatory breast cancer: clinical syndrome and molecular determinants. Breast Cancer Res 2000; 2:423.
- Rosen PP. Rosen's Breast Pathology, Lippincott-Raven, Philadelphia 1996.
- Robbins GF, Shah J, Rosen P, et al. Inflammatory carcinoma of the breast. Surg Clin North Am 1974; 54:801.
- Gruber G, Ciriolo M, Altermatt HJ, et al. Prognosis of dermal lymphatic invasion with or without clinical signs of inflammatory breast cancer. Int J Cancer 2004; 109:144.
- Lê MG, Arriagada R, Contesso G, et al. Dermal lymphatic emboli in inflammatory and noninflammatory breast cancer: a French-Tunisian joint study in 337 patients. Clin Breast Cancer 2005; 6:439.
- McCarthy NJ, Yang X, Linnoila IR, et al. Microvessel density, expression of estrogen receptor alpha, MIB-1, p53, and c-erbB-2 in inflammatory breast cancer. Clin Cancer Res 2002; 8:3857.
- Colpaert CG, Vermeulen PB, Benoy I, et al. Inflammatory breast cancer shows angiogenesis with high endothelial proliferation rate and strong E-cadherin expression. Br J Cancer 2003; 88:718.
- Koh EH, Buzdar AU, Ames FC, et al. Inflammatory carcinoma of the breast: results of a combined-modality approach--M.D. Anderson Cancer Center experience. Cancer Chemother Pharmacol 1990; 27:94.
- Paradiso A, Tommasi S, Brandi M, et al. Cell kinetics and hormonal receptor status in inflammatory breast carcinoma. Comparison with locally advanced disease. Cancer 1989; 64:1922.
- Nguyen DM, Sam K, Tsimelzon A, et al. Molecular heterogeneity of inflammatory breast cancer: a hyperproliferative phenotype. Clin Cancer Res 2006; 12:5047.
- Robertson JF, Ellis IO, Pearson D, et al. Biological factors of prognostic significance in locally advanced breast cancer. Breast Cancer Res Treat 1994; 29:259.
- Guérin M, Sheng ZM, Andrieu N, Riou G. Strong association between c-myb and oestrogen-receptor expression in human breast cancer. Oncogene 1990; 5:131.
- Lerebours F, Bertheau P, Bieche I, et al. Evidence of chromosome regions and gene involvement in inflammatory breast cancer. Int J Cancer 2002; 102:618.
- Lerebours F, Bertheau P, Bieche I, et al. Two prognostic groups of inflammatory breast cancer have distinct genotypes. Clin Cancer Res 2003; 9:4184.
- Moll UM, Riou G, Levine AJ. Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion. Proc Natl Acad Sci U S A 1992; 89:7262.
- Davidoff AM, Humphrey PA, Iglehart JD, Marks JR. Genetic basis for p53 overexpression in human breast cancer. Proc Natl Acad Sci U S A 1991; 88:5006.
- Riou G, Lê MG, Travagli JP, et al. Poor prognosis of p53 gene mutation and nuclear overexpression of p53 protein in inflammatory breast carcinoma. J Natl Cancer Inst 1993; 85:1765.
- Faille A, De Cremoux P, Extra JM, et al. p53 mutations and overexpression in locally advanced breast cancers. Br J Cancer 1994; 69:1145.
- van Golen KL, Davies S, Wu ZF, et al. A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin Cancer Res 1999; 5:2511.
- Ridley AJ. The GTP-binding protein Rho. Int J Biochem Cell Biol 1997; 29:1225.
- Nobes CD, Hall A. Rho GTPases control polarity, protrusion, and adhesion during cell movement. J Cell Biol 1999; 144:1235.
- Hall A. Rho GTPases and the actin cytoskeleton. Science 1998; 279:509.
- van Golen KL, Wu ZF, Qiao XT, et al. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res 2000; 60:5832.
- van Golen KL, Wu ZF, Qiao XT, et al. RhoC GTPase overexpression modulates induction of angiogenic factors in breast cells. Neoplasia 2000; 2:418.
- Suwa H, Ohshio G, Imamura T, et al. Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas. Br J Cancer 1998; 77:147.
- Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev 1999; 20:761.
- Clemmons DR. Role of insulin-like growth factor binding proteins in controlling IGF actions. Mol Cell Endocrinol 1998; 140:19.
- Oh Y. IGF-independent regulation of breast cancer growth by IGF binding proteins. Breast Cancer Res Treat 1998; 47:283.
- Burger AM, Zhang X, Li H, et al. Down-regulation of T1A12/mac25, a novel insulin-like growth factor binding protein related gene, is associated with disease progression in breast carcinomas. Oncogene 1998; 16:2459.
- Sprenger CC, Damon SE, Hwa V, et al. Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a potential tumor suppressor protein for prostate cancer. Cancer Res 1999; 59:2370.
- Kleer CG, Zhang Y, Pan Q, et al. WISP3 is a novel tumor suppressor gene of inflammatory breast cancer. Oncogene 2002; 21:3172.
- Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001; 7:192.
- Stacker SA, Caesar C, Baldwin ME, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001; 7:186.
- Kurebayashi J, Otsuki T, Kunisue H, et al. Expression of vascular endothelial growth factor (VEGF) family members in breast cancer. Jpn J Cancer Res 1999; 90:977.