Inflammatory Breast Cancer

Etiology

A high body mass index is an independent risk factor for inflammatory breast cancer. Possible risk factors that need further investigation are viral infections and chronic inflammation, younger age at first live birth, smoking, and breastfeeding.[2] Inherited genetic mutations and family history have demonstrated no association.

Epidemiology

Based on the data from the surveillance, epidemiology, and end results (SEER) program of the National Cancer Institute, throughout the 1990s, IBC incidence rose, and survival improved modestly. Substantial racial differences were noted in age at diagnosis, age-specific incidence rates, and survival outcomes.[3] The incidence of IBC has remained essentially stable for nearly two decades, from 1990 to 2002.[4] 

Inflammatory breast cancer is the most aggressive entity of breast cancer. The median overall survival among women is less than 4 years, even with multimodality treatment options. However, increased survival in recent years has been noted with the improvement of chemotherapeutic management.[5] Ethnicity is an independent predictor of elevated risk for breast cancer mortality, and social-economic status is an independent predictor of advanced age at the diagnosis.[6] 

Several studies have reported that inflammatory breast cancer constitutes a larger proportion of breast cancers in low-income countries than in Western countries. Management of inflammatory breast cancer in low-income countries poses different sets of challenges, including poor access to screening, late stage of presentation, and poor availability of multidisciplinary services.[7] The incidence of IBC is higher in Black women when compared to Whites.

Pathophysiology

An angioinvasive nature is intrinsic to primary IBC. Normal experimental studies have evaluated the role of hormone receptor status and genetic changes, the p53 tumor suppressor gene, cytokines, and other genetic determinants.

Hormone receptors and other tumor markers: The majority of IBCs are hormone receptor-negative. Breast cancers with negative estrogen receptors (ER) and progesterone receptors (PGR) are generally associated with shorter disease-free survival and poor prognosis than receptor-positive tumors. IBCs also have high proliferative rates and also overexpress human epidermal growth factor receptor 2 (HER 2). These molecular markers may identify patients who have a worse prognosis.

Genetic changes: At least half of IBCs have a loss of heterozygosity. The most frequent lost alleles are 17 q., 13 q., 11 q., 8P, 6P, and 3P.[8]

P53 tumor suppressor gene (TSG): Accumulation of p53 protein or mutation in p53 TSG was reported in 20% to 50% of human breast cancers. These abnormalities are often seen in hereditary breast cancer syndromes like familial breast and ovarian cancers (e.g., Li-Fraumeni syndrome).  Multiple observational study findings showed that patients with P53 gene mutation and nuclear overexpression was associated with the larger tumor size and disseminated disease at the time of diagnosis and had 8.6 fold higher risk of death compared with patients that do not have this mutation.[9] A simultaneous important prognostic interaction with ER expression is also noted. Patients with both ER-negative and a p53 overexpression had an 18 fold higher risk of death compared to 2.8 fold for women with p 53 nuclear overexpression alone.

New gene mutations: The RhoC GTPase oncogene was more often overexpressed (90 versus 38 percent), and WNT1-inducible-signaling pathway protein 3 (WISP3) was commonly lost in the IBCs (80 versus 21 percent).[10]

Cytokines: IBC is a misnomer, it produces negligible levels of most inflammatory cytokines such as interleukin-12, interleukin-1, and interferon-gamma. Inflammatory breast cancer tends to be highly vascular because of its angiogenic and angioinvasive potential. They release increased amounts of vascular endothelial growth factor, fibroblast growth factor, and interleukin-6 and 8. These cytokines are increasingly released in human mammary epithelial cells that are transfected with the overexpression of the RhoC GTPase gene, which is specifically associated with IBC. Activation of vascular endothelial growth factor-3, particularly by VEGF-D in IBC, is involved in lymphotactic process through the development of new lymphatic vessels near the tumor.

Histopathology

IBC is a clinicopathological diagnosis that requires an interprofessional approach for diagnosis.[11] A core needle biopsy of the breast should be obtained to make the initial diagnosis of invasive carcinoma. The classic histologic finding in inflammatory breast cancer on biopsy of the affected skin is dermal lymphatic invasion by tumor cells. The same malignant cells from tumor emboli are responsible for local and metastatic disease.

Several things need to be kept in mind when evaluating the skin biopsy:

1. Dermal lymphatic invasion (DLI) is not always found in patients with primary inflammatory breast cancer, this is likely due to sampling error.
2. DLI can be an incidental finding in patients with breast cancer who do not have clinical evidence of IBC. These tumors are not considered to be inflammatory cancers.
3. Other disorders like acute mastitis, infiltrated lymphoma or leukemia, and advanced breast cancers can also have similar clinical features.[12]

History and Physical

Patients with inflammatory breast cancer typically present with pain or a rapidly growing breast lump associated with itching and enlargement of the breast. Almost all have lymph node involvement at the time of presentation, and about one-third will have distant metastasis. Therefore, some may present with swollen lymph nodes or localizing pain depending on the location and extent of the disease.

The onset of symptoms is rapid, ranging from weeks to months. Most patients are initially treated with antibiotics for presumed mastitis or abscess and seek expert advice after no clinical improvement. Unfortunately, an abnormal screening mammogram constitutes about 10% of cases at presentation.

On examination, the breast shape might be distorted or enlarged, and the skin appears like the skin of an orange (Peau d'orange), warm and thick to touch. Nipple involvement is seen as crusting, erythema, flattening, blisters, or retraction of the nipple. A discrete palpable mass may or may not be present. A detailed examination of both breasts and axilla should be performed for local lymph node involvement.

Evaluation

The diagnosis of inflammatory breast cancer is based upon the characteristic clinical presentation and core needle biopsy showing invasive carcinoma of the breast. A very high index of suspicion should be present when evaluating a patient who presents with rapidly progressive inflammatory skin changes of the breast with no improvement with antibiotics. Patients with suspected inflammatory breast cancer should undergo breast imaging and biopsy.

A mammogram is the first imaging test in the evaluation of inflammatory breast cancer. A diagnostic mammogram should be used on the affected side and a screening mammogram on the contralateral side. An ultrasonogram of both the breasts and regional lymph nodes should be done for suspected malignancy. Mammographic findings of inflammatory breast cancer may include an obvious mass, a large area of calcification, or parenchymal distortion with skin thickening. Mastitis and inflammatory breast cancer without an underlying mass may have a similar mammographic appearance. If there is no improvement after a short course of antibiotics (usually less than a week), a biopsy should be done to rule out underlying malignancy.

Ultrasonography might show thickened skin, interstitial fluid, and disruption of normal tissue planes of the involved breast. It may be useful to characterize the masses, guide in the percutaneous biopsy, and lymph node biopsies.

The imaging features of IBC on conventional imaging using mammography and ultrasound are nonspecific, likely secondary to the considerable edema and erythema that are hallmarks of this disease. The compression necessary for a good mammography examination may not be well tolerated by patients with IBC. Suboptimal tissue compression, in combination with diffuse skin and trabecular thickening, and tissue edema may obscure masses on mammography. Likewise, diffuse tissue edema and parenchymal architectural distortion may increase the challenge of identifying a primary breast lesion with ultrasound to facilitate core needle biopsy.

Multiple small, confluent, heterogeneously enhancing masses and global skin thickening are key magnetic resonance imaging (MRI) features of IBC that contribute to improved detection of primary breast cancer and delineation of disease extent compared with mammography.[13] In difficult cases, MRI may help in guiding skin punch biopsies. It is also used to monitor response to chemotherapy. MRI is the most accurate imaging technique in detecting primary breast parenchymal lesions in IBC patients. Sonography can be useful in diagnosing regional nodal disease.

Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan provides additional information regarding lymph nodes or distant metastases in the initial evaluation of IBC. PET scan is used to stage and differentiate between the curable and incurable state of cancer and assess response to therapy.[14]

As with other invasive breast cancers, all IBC tumors should undergo testing for hormone receptors and human epidermal growth factor receptor 2 (HER2).

Treatment / Management

Both national comprehensive cancer network and international inflammatory breast cancer expert guidelines recommend intensive therapy for patients with primary inflammatory breast cancer to achieve the best local control and survival outcome via a tri-modality approach: Systemic therapy, surgery, and radiation therapy. An interprofessional team approach is critical in the care of patients with inflammatory breast cancer.[15](B3)

Nonmetastatic IBC-stage III 

The treatment of nonmetastatic inflammatory breast cancer is similar to nonmetastatic noninflammatory locally advanced breast cancer (LABC). The major difference is that sentinel lymph node biopsy and breast conservative therapy are not preferred in IBC even with a very good response to neoadjuvant therapy. All eligible patients should be enrolled in clinical trials, given the rarity of the disease.

The standard therapy includes neoadjuvant chemotherapy, followed by locoregional treatment (grade 1B). All patients who have achieved a partial response to neoadjuvant chemotherapy should undergo modified radical mastectomy with axillary dissection and post-mastectomy radiation. For nonsurgical candidates, radiotherapy is given. The success of systemic therapy in stage III inflammatory breast cancer is measured by the pathologic response to the therapy. Patients that have achieved pathologic complete response have significantly improved outcomes compared with those who did not.

Anthracycline and taxane-based chemotherapy regimens are commonly used in neoadjuvant therapy. For inflammatory breast cancer with HER-2 overexpression, trastuzumab with or without pertuzumab is used in addition to neoadjuvant chemotherapy. Trastuzumab should be continued for a total period of 1 year. To minimize the cardiotoxicity, anthracyclines are given first, followed by taxanes and trastuzumab. For hormone receptor-positive, postmenopausal women, aromatase inhibitors like anastrozole is used for 5 years. (Grade 2 A). For premenopausal women that are hormone receptor-positive, ovarian function suppression plus tamoxifen for a period of 10 years (grade 2B) is used.

Inflammatory breast cancer is associated with poor prognosis and a high risk of early recurrence, so immediate reconstruction following surgery should be avoided. New evidence suggests that outcomes have improved with neoadjuvant chemotherapy, followed by local, regional treatment.

Metastatic IBC-stage IV

About one-third of patients with inflammatory breast cancer at the time of diagnosis have stage IV disease. The treatment for metastatic disease is primary systemic therapy to achieve optimal response. For patients who have a significant clinical response after systemic therapy, every effort should be given for intense locoregional therapy. Controversy exists about the impact of surgery and radiation therapy in terms of overall survival in this population. The goal of systemic treatment for metastatic inflammatory breast cancer is a prolongation of survival, symptom elevation, maintenance, and improvement in the quality of life despite the toxicities associated with treatment as local progression is an issue.

Differential Diagnosis

Several conditions may be confused with inflammatory breast cancer. Extreme caution should be used as this may lead to potentially preventable delays in diagnosis and treatment.

• Ductal ectasia- This is a benign condition in a middle-aged woman, related to the collection of skin debris and swelling of the ducts. It improves without treatment.
• Infectious mastitis and breast abscess- Infections of the breast in a lactating mother is associated with fever and leukocytosis, typically improves with antibiotics, but can have a similar examination and mammographic findings.
• Noninflammatory breast cancer- It is difficult to differentiate inflammatory breast cancer from noninflammatory, locally advanced breast cancer that involves the skin. Skin dimpling, nipple retraction, satellite skin nodules, edema of the skin, ulceration alone without other diagnostic criteria do not qualify as inflammatory breast cancer.
• Other malignancies like breast lymphoma or leukemia may also present similar to inflammatory breast cancer. They can be differentiated with biopsy and histologic findings.

Prognosis

Inflammatory breast cancer is associated with very poor prognosis and a high risk of early recurrence. The current evidence suggests that for the same stage of locally advanced breast cancer, inflammatory breast cancer has a poorer prognosis. The factors which suggest poor prognosis are negative receptor status, 4 or more lymph node involvement at the time of presentation, and lack of response to neoadjuvant chemotherapy. With the advent of tri-modality treatment, current overall 5-year survival rates range from 30% to 70%.

Complications

The most common complications of inflammatory breast cancer are from local and distant metastasis. They include severe pain, including bone and nerve pain. Metastasis to the bone can also lead to hypercalcemia resulting in kidney stones, neurological complications like confusion, coma, memory problems, and arrhythmias. About half of the patients with metastatic breast cancer have liver lesions. It can cause significant abdominal discomfort, nausea, vomiting, and jaundice. As the disease progresses, the patient will have a poor appetite and weight loss. Metastasis to the brain may affect vision, behavioral and memory problems and causes progressive worsening headache.

Chemotherapy related complications include oral ulcers, nausea, and diarrhea. Surgery-related complications include risk of surgery, risk of anesthesia, infection, poor healing, and cosmetic appearance. Lymphedema is a dreadful complication of axillary lymph node dissection. Radiation therapy can cause severe pain and scarring.

Inflammatory breast cancer causes significant stress on the social and economic life of the patient and their families.