Inflammatory breast cancer

The lifetime risk of breast cancer in the United States has now risen to one in eight women.(1) Since inflammatory breast cancer constitutes approximately 2 percent of all malignant breast tumors,(2) the number of women currently at risk for inflammatory breast cancer is significant, based on an estimated 182,000 new cases among women in the United States in 1995.(1) Breast cancer rates have actually increased roughly 2 percent per year since the early 1970s.(1) Such a large number of women at risk emphasizes the importance of formal recommendations regarding the diagnosis of inflammatory breast cancer.

The differential diagnosis of an inflamed breast in a lactating woman includes acute mastitis, abscess, tuberculosis (uncommon) and, rarely, cancer. The differential diagnosis of an inflamed breast in a nonlactating woman includes inflammatory breast cancer, duct ectasia(3) (synonyms include plasma cell mastitis and nonlactational chronic breast abscess(4)), lymphoma and generalized dermatitis (insect bites, sunburn and allergic reactions(5)).(1)

Duct ectasia occurs primarily in older women,(3) and if the (usually localized) area of erythema does not improve rapidly with conservative treatment,(5) excision of the involved ductal system may be required.(6) Inflammatory breast cancer usually involves at least one-third of the breast tissue and is poorly demarcated, while duct ectasia is typically well-circumscribed and affects less than one-third of the breast.(5)

Given the grave prognosis for patients with inflammatory breast cancer, diagnosis must not be delayed through prolonged use of antibiotics during treatment for presumed mastitis. Any significant delay in the diagnosis and treatment of inflammatory breast cancer may have potentially catastrophic consequences for the patient and may place the physician in legal jeopardy.

Timely diagnosis has the advantage of a potentially improved prognosis: patients with clinically negative axillary nodes typically fare better than patients with involved axillary nodes (median survival of 90 months and 25 months, respectively).(7) Thus, the diagnosis and treatment of inflammatory breast cancer at an earlier stage should enhance the patient's chances of survival.

Infections of the female breast are uncommon, except during the postpartum period. Conversely, inflammatory breast cancer is rare in lactating women and typically occurs in patients with a mean age of 50 to 55 years, although it can occur in women as young as 35 years of age.(3)(5) Breast inflammation in an older, nonlactating woman should raise the suspicion of inflammatory breast cancer. An algorithm for the management of patients presenting with an inflamed erythematous breast is presented in Figure 1.

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Acute Mastitis

Puerperal mastitis usually occurs after a first pregnancy and consists of a localized area of inflammation, warmth and tenderness.(6) Consequently, the patient may present in the second and third weeks of lactation with a localized, painful lump in the breast associated with local edema(8) and, often, systemic symptoms such as fever and leukocytosis.(3)

In contrast, inflammatory breast cancer is rarely associated with a significant fever and/or leukocytosis (Table 1). Nipple discharge can be associated with benign and malignant conditions and, therefore, does not constitute a diagnosis of inflammatory breast cancer.

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The most common organism causing puerperal mastitis is Staphylococcus aureus.(6) A penicillinase-resistant penicillin, in conjunction with emptying of the breast, should be promptly initiated.(4) In cases of early mastitis, some authorities recommend the patient increase the frequency of breast feeding, while in cases of mastitis associated with an abscess, as evidenced by ultrasonography or by detection of a fluctuant mass on physical examination, many clinicians favor discontinuation of nursing and use of bromocriptine (Parlodel) to decrease lactation.(9) If the patient is allergic to penicillin, alternative antibiotic choices include the cephalosporins, particularly a first-generation cephalosporin.(9) The clinician should be aware of the potential for cross-sensitivity between penicillins and cephalosporins.

Supportive treatment, including the application of heat, should result in improvement of the patient's symptoms within a few days. If the patient's symptoms do not respond, the physician must consider the possibility of a breast abscess or inflammatory breast cancer. If an abscess is diagnosed, surgical drainage is appropriate.

Common organisms in mastitis associated with abscess include S. aureus and anaerobes such as Bacteroides and Peptostreptococcus. Therefore, appropriate antibiotics include clindamycin (Cleocin) or a combined regimen of a penicillinase-resistant penicillin/first-generation cephalosporin plus metronidazole (Flagyl).(9) When intravenous antibiotics are indicated, ampicillin-sulbactam (Unasyn) or vancomycin (Vancocin, Vancoled) plus metronidazole is appropriate. When an abscess is the cause of breast inflammation, biopsy yields pus rather than the hemorrhagic tissue yielded in cases of inflammatory breast cancer (which should also show carcinoma on a frozen section).(3)

Because of its rapidly progressive course, an aggressive approach to the diagnosis and treatment of inflammatory breast cancer is warranted. Thus, we recommend that further evaluation with mammography and biopsy be strongly considered if a significant clinical improvement in breast inflammation is not noted within seven to 10 days.(10) The biopsy should include a small piece of skin and may demonstrate dermal lymphatic invasion, although this finding is not mandatory for the diagnosis of inflammatory breast cancer.(11)

Inflammatory Breast Cancer

Most patients with inflammatory breast cancer note pain, tenderness and firmness of the breast and an increase in breast size. Typically, within four weeks of the onset of symptoms, the skin becomes warm, red, raised, heavy, hard, painful and edematous (Figure 2). The edema is often described by patients as a roughening or thickening of the skin (i.e., peau d'orange appearance) of the breast.(3)(12)

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The clinician may note either an erythematous discoloration of the entire breast, a localized area of erythema, or erythema of inflammatory breast cancer initially occurs over the lower, dependent half of the breast and may appear at first as a mottled pink color, which may subsequently become uniform over the entire breast.(3) The nipple is often flattened and retracted and, as the disease progresses, the nipple epithelium may become reddened and crusted.(3).

If medical treatment of inflammatory breast cancer is delayed, most patients have axillary metastases when first examined.(3) An aggressive diagnostic approach is therefore warranted to improve the dismal prognosis of patients with inflammatory breast cancer.

DIAGNOSTIC STUDIES

Characteristic mammographic findings in patients with inflammatory breast cancer include a dense, poorly demarcated infiltration over a wide area with increased vascularity and skin thickening caused by direct tumor invasion or permeation along subdermal lymphatics, resulting in cutaneous lymphedema.(2) However, mammograms may not reveal anything truly characteristic of inflammatory breast cancer and, since inflammatory symptoms lack specificity, mammographic findings should be viewed as supportive only and not as diagnostic of inflammatory breast cancer.(3) Although inflammatory breast cancer occurs rarely during pregnancy and lactation, the diagnosis should still be kept in mind.(6) Physicians must also consider the possibility of an infection coincident with breast malignancy, which could pose an obvious difficulty in establishing an accurate diagnosis.(13)

The initial diagnosis of inflammatory breast cancer is primarily clinical, supported by histologic data. Fine-needle aspiration biopsy or incisional biopsy helps to confirm the diagnosis by demonstrating malignant cells. Demonstration of tumor emboli in dermal lymphatics is not required for the diagnosis of inflammatory breast cancer,(14) but their presence should heighten the clinician's suspicion for inflammatory breast cancer.

TREATMENT

A combined modality approach generally begins with chemotherapy.(10)(11)(15)(16) Systemic therapy, usually based on doxorubicin (Adriamycin, Rubex), provides the advantage of in vivo determination of tumor chemosensitivity and reduction in tumor bulk (for most patients) and may make operable some tumors that previously had been inoperable.(17) The surgical procedure most often chosen is a modified radical mastectomy. Pathologic evaluation of the specimen may provide prognostic information.

The optimal treatment strategy and schedule for inflammatory breast cancer are not yet clear, but a multi-modality approach, including chemotherapy, surgery and radiation therapy, appears to be the most efficacious therapeutic alternative at present. Clinical trial enrollment of patients with inflammatory breast cancer is required to further establish the best approach to treatment.

Final Comment

Inflammatory breast cancer is a devastating disease that progresses at an alarming rate. Most patients with inflammatory breast cancer die as a result of distant metastases, whether or not local or regional control was obtained within the first two years of diagnosis.(14) Thus, the primary care physician needs to promptly establish an accurate diagnosis of inflammatory breast cancer if the subsequent referrals to specialists and treatment regimens are to be effective in improving the patient's already poor prognosis.

REFERENCES

(1.)Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. CA Cancer J Clin 1995; 45:8-30 [Published erratum appears in CA Cancer J Clin 1995; 45:127-8].

(2.)Parsons CA, ed. Diagnosis of breast disease: imaging, clinical features and pathology. London: Chapman and Hall, 1983:152.

(3.)Bland KI, Copeland EM 3d, eds. The breast: comprehensive management of benign and malignant diseases. Philadelphia: Saunders, 1991.

(4.)Marchant DJ, Kase NG, Berkowitz RL. Breast disease. New York: Churchill-Livingstone, 1986:160-1.

(5.)Abrams JS, Aisner J. The evolving approach to stage III breast cancer. In: Kennedy BJ, ed. Breast cancer. New York: Liss, 1989:151.

(6.)Haagensen CD. Diseases of the breast. 3d ed. Philadelphia: Saunders, 1986:808-11.

(7.)Henderson MA, McBride CM. Secondary inflammatory breast cancer: treatment options. South Med J 1988; 81:1512-7.

(8.)Rogers K. Breast abscesses and problems with lactation. In: Smallwood JA, Taylor I, eds. Benign breast disease. Baltimore: Urban & Schwarzenberg, 1990:106.

(9.)Sanford JP. Guide to antimicrobial therapy. West Bethesda, Md.: Antimicrobial Therapy, Inc., 1991:3.

(10.)Ferrara JJ, Leveque J, Dyess DL, Lorino CO. Nonsurgical management of breast infections in nonlactating women. A word of caution. Am Surg 1990; 56:668-71.

(11.)Jaiyesimi IA, Buzdar AU, Hortobagyi G. Inflammatory breast cancer: a review. J Clin Oncol 1992; 10:1014-24.

(12.)Lucas FV, Perez-Mesa C. Inflammatory carcinoma of the breast. Cancer 1978; 41:1595-605.

(13.)De Lena M, Zucali R, Viganotti G, Valagussa P, Bonadonna G. Combined chemotherapy-radiotherapy approach in locally advanced (T3b-T4) breast cancer. Cancer Chemother Pharmacol 1978; 1:53-9.

(14.)Zylberberg B, Salat-Baroux J, Ravina JH, Dormont D, Amiel JP, Diebold P, et al. Initial chemoimmunotherapy in inflammatory carcinoma of the breast. Cancer 1982; 49:1537-43.

(15.)Loprinzi CL, Carbone PP, Tormey DC, Rosenbaum PR, Caldwell W, Kline JC, et al. Aggressive combined modality therapy for advanced local-regional breast carcinoma. J Clin Oncol 1984; 2:157-63.

(16.)Thoms WW Jr, McNeese MD, Fletcher GH, Buzdar AU, Singletary SE, Oswald MJ. Multimodal treatment for inflammatory breast cancer. Int J Radiat Oncol Biol Phys 1989; 17:739-45.

(17.)Buzdar AV, Hortobagyi GN, McNeese M, Anderson MD, et al. Combined modality approach in treatment of inflammatory carcinoma of the breast [Abstract]. In: Proceedings of the 3rd International Congress on Neo-Adjuvant Chemotherapy. New York: Springer Verlag, 1991.

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