Approach to inflammatory breast cancer

Case 1

Callie is a 36-year-old who gave birth to her first child 2 months ago. Five days ago she noticed redness and tenderness in her left breast. She has no relevant personal past medical history; however, her mother and maternal aunt were both diagnosed with breast cancer in their 60s. Callie presents to your office with visible erythema of the left breast in the upper outer quadrant and concomitant tenderness. She is concerned about infection and breast-feeding on that side. Should you be concerned about IBC?

Case 2

Edith is a 76-year-old widow. She presents to your office complaining of a 3-month history of enlargement of the right breast. Physical examination reveals that her right breast is enlarged and red, and the skin is firm, with pitting (Figure 1). She has palpable axillary lymph nodes. You suspect IBC. What are your next steps in diagnosis and management?

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Figure 1

Right breast is enlarged and red, and the skin is firm, with pitting

Sources of information

Data for this review were identified by a search of MEDLINE (January 1950 to April 2008) using search terms inflammatory breast cancer, detection, differential, risk factors, family physician, and survival. References were hand-searched for relevance and limited to English-language articles. Evidence is level II (epidemiologic studies) and III (reviews based on retrospective case series and expert opinions).

Definition

Inflammatory breast cancer is a clinical diagnosis. Patients typically present with a rapidly progressing, tender, firm, enlarged breast (Table 1). This presentation is due to the invasion of skin dermal lymphatics by breast cancer cells. The obstructed lymph channels produce characteristic skin changes—erythema, warmth, edema, and induration—that mimic an inflammatory process, except cancer cells rather than inflammatory infiltrate are seen under the microscope.4 These changes are sometimes, but not always, demonstrated on skin biopsy.

Epidemiology

Inflammatory breast cancer is not common, representing anywhere from 1% to 6% of all breast cancer diagnoses (level II evidence).5 A recent review suggested that the incidence of IBC could be rising; authors found an incidence of 2% from 1988 to 1990 and 2.5% from 1997 to 1999.5

Inflammatory breast cancer is more common among black women and is associated with younger age at diagnosis (mean age 50 to 58 years compared with 50 to 64 years among those diagnosed with noninflammatory breast cancer).6 Studies based on cases in North Africa, where for unknown reasons 50% of breast cancer cases present as IBC, have suggested an association with obesity and younger age at first giving birth.6 However, there are no validated risk factors that might aid in raising suspicion for IBC.6,7

Inflammatory breast cancer is commonly diagnosed in women who have never had breast cancer, but it can also develop in a breast that contains a known tumour or that has been previously treated. These “secondary” cases of IBC behave similarly to “primary” cases of IBC, and therefore a diagnosis of IBC cannot be excluded in a woman with a known history of breast cancer.8

Clinical presentation

Patients with IBC usually present with a complaint of colour change in 1 breast, usually pink that evolves into a darker red and spreads over the entire breast. The patient might describe a sensation of heat in the breast, and the breast itself enlarges rapidly over a period of only a few weeks (Table 1 and Figure 2). Patients usually do not experience fever.9

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Figure 2 Patients with inflammatory breast cancer

Patients usually present complaining of colour change in one breast, usually pink that evolves into a darker red and spreads over the entire breast. The patient might describe a sensation of heat in the breast, and the breast itself enlarges rapidly.

Physical examination should focus on assessing warmth, swelling, induration, erythema, and peau d’orange. Nipple changes such as crusting and retraction might be seen but are not criteria for diagnosis.9 Underlying tumour masses might be palpable in IBC, but up to 30% of patients will present with no underlying masses. Instead, such a patient will have a diffusely enlarged breast.9 Given the rapid spread of this type of tumour, it is not uncommon to find axillary adenopathy. Rarely, patients might have signs or symptoms of metastatic spread (Table 2).

Certain warning signs in a woman with a red breast increase the likelihood of IBC (Table 3). These include a personal history of breast cancer, nonlactational status, and palpable axillary adenopathy. Unless a clear alternative diagnosis is present, these women should be referred immediately to surgical oncologists.

Differential diagnoses

The differential diagnoses for inflammation of the breast include benign diseases and other malignancies, and can be stratified by lactation status (Table 4).

Lactation mastitis occurs in up to 10% of lactating women and is associated with localized tenderness, fever, and leukocytosis—features that help to distinguish it from IBC.10 Mastitis develops rapidly over a few days. The erythema is associated with tenderness and occupies a wedge-shaped quadrant of the breast, and the patient feels unwell. Infection is usually caused by Staphylococcus aureus and improvement occurs within 24 to 48 hours of initiating antibiotics.

Duct ectasia is a benign entity of the nonlactating breast that affects perimenopausal and postmenopausal women. It occurs when ducts beneath the nipples become clogged with fatty material, producing a lump. There is frequently itching or burning around the nipple and a thick discharge.11 These changes are well demarcated and involve less than one-third of the breast.12 Duct ectasia is usually a self-limited disease but might lead to subareolar abscesses that require surgical resection.11

Other benign entities that can be confused with IBC include Mondor disease and fat necrosis. Mondor disease, or phlebitis of the thoracoepigastric vein, usually presents as a painful, possibly palpable, cord and is usually preceded by trauma.10 Because there is a possible association with malignancy, a mammogram is suggested for women older than 35 years of age. Treatment includes reassurance and nonsteroidal anti-inflammatory drugs. Fat necrosis can occur spontaneously or as a result of trauma.10 The usual presentation of fat necrosis is a palpable lump, and a biopsy might be required to differentiate it from malignancy. Neither Mondor disease nor fat necrosis will result in enlarged lymph nodes, another clue to diagnosis of IBC.11

Malignant entities that mimic IBC include leukemic infiltration of the breast. These patients are usually systemically unwell, and a peripheral blood smear usually confirms this rare diagnosis.

Generally, benign breast conditions will resolve with appropriate treatment. Most experts recommend waiting 7 days before initiating further investigations, unless the clinical suspicion of IBC is high (classic breast appearance, axillary nodes, no history of lactation or trauma).

Investigations

If clinical suspicion of IBC is high, prompt referral to a surgeon should be made. Otherwise the first investigation ordered is generally a mammogram. The classic changes that can be seen on a mammogram in IBC are skin thickening, trabecular and stromal thickening, and increased breast density.13 Inflammatory breast cancer, as mentioned, might not be associated with a breast mass, and concomitant high breast density can obscure masses as well; therefore, absence of suspicious masses on the mammogram is not helpful in ruling out IBC.

Ultrasound of the breast and axillary lymph nodes can be useful when IBC is suspected. Ultrasound imaging might detect masses that were not obvious on palpation or mammography, or reveal axillary adenopathy, and thereby facilitate biopsy for diagnosis.13

If results of these investigations do not suggest a benign diagnosis (such as fat necrosis), and the patient’s symptoms persist beyond 3 weeks despite appropriate investigations and conservative treatment (such as nonsteroidal anti-inflammatory drugs and antibiotics), prompt referral to a surgeon is necessary.

Management

Patients with IBC need to be treated promptly, ideally in a multidisciplinary breast oncology clinic that specializes in the treatment of IBC. This patient group requires coordination of medical, surgical, and radiation oncology care as well as nursing and other supportive disciplines. These clinics are usually only found within cancer centres affiliated with tertiary hospitals, and might require patients to travel substantial distances.

Management of IBC encompasses combined-modality therapy. Owing to the skin involvement of IBC, the risk of loco-regional and distant recurrence is too high to justify immediate mastectomy. Preoperative chemotherapy is therefore standard care.14 Before initiating chemotherapy, a core biopsy is performed to confirm the diagnosis and determine hormone-receptor and HER-2/neu status of the tumour. A metastatic workup completes staging. This workup includes bone scans, chest x-ray scans, and abdominal ultrasound scans (with more focused tests if there are any additional symptoms).

The purpose of chemotherapy up front (also known as neoadjuvant or preoperative chemotherapy) is to eliminate micrometastatic disease and reduce inflammation in the breast, making tumours amenable to surgery and radiation. Response to chemotherapy also tells oncologists about the aggressiveness of tumours, providing clues to patients’ ultimate prognoses. After chemotherapy, patients undergo mastectomy and axillary lymph node dissection, followed by radiation therapy to the chest wall and regional lymph nodes.15 The final component of treatment includes endocrine therapy and targeted therapy, such as trastuzumab, depending on receptor status. In total, the active treatment of IBC takes about 1 year.

Common side effects of chemotherapy include alopecia, nausea and vomiting, and risk of febrile neutropenia. Patients are advised to promptly visit the nearest emergency department if they experience a fever (higher than 38°C for at least 1 hour, or 1 reading above 38.2°C). Some patients receiving taxane chemotherapy experience bony pain or myalgias. This pain often responds to treatment with acetaminophen, but can be severe enough to require opioid treatment as well.16 Long-term effects include increased risk of cardiac damage (due to anthracycline therapy) and increased risk of leukemia.

Prognosis

When compared with other breast cancer patients presenting at the same stage, women with IBC have worse prognoses. Moreover, up to 25% of women present with metastatic, incurable disease.17 Median overall survival for IBC patients is 2.9 to 4.2 years,18,19 with lower survival rates among black women and those with estrogen receptor–negative tumours.5 These survival rates have not changed significantly over the past 30 years, emphasizing the aggressive nature of the disease.19 Newer biologic agents such as trastuzumab and lapatinib might improve outcomes for patients with IBC.14 Given the baseline poor prognosis of IBC, eligible patients are offered inclusion in clinical trials if possible.

Family physicians’ role in management

Family physicians are gatekeepers: they play a crucial role in identifying IBC and referring patients appropriately. The oncology team treats the cancer and related problems; however, the family doctor manages nononcologic diagnoses that were present before diagnosis of IBC. Some conditions might be affected by treatment; for instance, blood-glucose control in patients with diabetes often worsens during chemotherapy, owing to steroids given adjunctively. The family doctor often needs to provide psychological support to the patient and her family. Once treatment is finished, close clinical surveillance and annual mammography are shared responsibilities of the oncologist and family doctor. The family doctor also monitors for long-term side effects of treatment (Table 5).

Often the family physician is not only the patient’s doctor but also her whole family’s doctor. If the patient is the primary caregiver in the family, a shifting of roles needs to occur, and coping can be difficult. Previous relationship difficulties are often exacerbated by the stress of a new diagnosis. Children of any age are substantially affected.20 Family physicians should inquire about children’s health and development; some warning signs include somatic complaints, difficulties with school, depression, and anxiety. Some families might benefit from multidisciplinary support teams that include family physicians, oncologists, nurses, and social workers. Internet resources can also be helpful (Table 6).

Given the poor prognosis of IBC, family doctors might need to help with palliative care as well. Communication with a patient’s oncologist is essential for optimizing symptom management and organizing end-of-life care. Palliative care clinics affiliated with cancer centres are excellent referral centres that organize home nursing and social work, and they will liaise with family doctors to provide comprehensive and consistent care.

Conclusion

Family physicians are uniquely positioned to assure timely diagnosis of IBC, which is an aggressive form of breast cancer. Prompt recognition of symptoms and signs suggestive of IBC, referral to a multidisciplinary team for treatment, and support of women and their families throughout treatment and beyond assures optimal management of this potentially fatal disease.

Case 1 resolution

Callie has a low-grade fever, and her baby is not feeding properly from the affected breast. Examination reveals a focal area of pain, redness, and induration in the outer upper quadrant, with no palpable lymphadenopathy. Bloodwork results show leukocytosis and left shift. You instruct Callie about compresses, ibuprofen, and continued breastfeeding, and prescribe a 14-day course of oral cloxacillin.11 You expect improvement within 48 hours; if there is no response within 7 days you will reconsider the diagnosis, perform a mammogram and an ultrasound, and, depending on the results, refer Callie to a breast cancer centre.

Case 2 resolution

Edith has many worrisome features of IBC, and prompt mammogram and ultrasound are performed. She is immediately referred to a tertiary oncology centre when pathology from the ultrasound-guided lymph node biopsy reveals breast adenocarcinoma. You help manage her pain and symptoms throughout her ordeal, but despite optimal treatment her cancer spreads and she dies peacefully, pain-free, at a hospice.